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Mahdi AF, Ashfield N, Crown J, Collins DM. Pre-Clinical Rationale for Amcenestrant Combinations in HER2+/ER+ Breast Cancer. Int J Mol Sci 2025; 26:460. [PMID: 39859174 PMCID: PMC11765389 DOI: 10.3390/ijms26020460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/19/2024] [Accepted: 12/27/2024] [Indexed: 01/30/2025] Open
Abstract
HER2-positive/oestrogen receptor-positive (HER2+/ER+) represents a unique breast cancer subtype. The use of individual HER2- or ER-targeting agents can lead to the acquisition of therapeutic resistance due to compensatory receptor crosstalk. New drug combinations targeting HER2 and ER could improve outcomes for patients with HER2+/ER+ breast cancer. In this study, the pre-clinical rationale is explored for combining amcenestrant (Amc), a selective oestrogen receptor degrader (SERD), with HER2-targeted therapies including trastuzumab, trastuzumab-emtansine (T-DM1) and tyrosine kinase inhibitors (TKIs). The combination of Amc and anti-HER2 therapies was investigated in a panel of four HER2+/ER+ cell lines: BT-474, MDA-MB-361, EFM-192a and a trastuzumab-resistant variant BT-474-T. Proliferation (IC50 and matrix combination assays) was determined using acid phosphatase assays. HER2/ER and intracellular signalling pathway protein levels/activity were investigated by western blot. Apoptosis was assessed using caspase 3/7 assays. Additivity and synergy were observed between Amc and the TKIs neratinib, lapatinib and tucatinib in all cell lines. Amc increased the anti-proliferative effect of trastuzumab in MDA-MB-361 and BT-474-T. Addition of Amc also increased anti-proliferative efficacy of T-DM1 in BT-474-T. TKI/Amc combinations reduced p-HER2 and ER levels and resulted in increased apoptosis. Higher ER expression in MDA-MB-361 and BT-474-T was associated with greater potential for synergy. In conclusion, the combination of Amc- and HER2-targeted treatments has potential as a therapeutic strategy for the treatment of HER2+/ER+ breast cancer and warrants further clinical investigation to validate safety and efficacy in patients.
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Affiliation(s)
- Amira F. Mahdi
- Cancer Biotherapeutics Research Group, Life Sciences Institute, School of Biotechnology, Dublin City University, Dublin 9, D09 NR58 Dublin, Ireland; (N.A.); (J.C.)
- Limerick Digital Cancer Research Centre, Health Research Institute, School of Medicine, University of Limerick, V94 T9PX Limerick, Ireland
| | - Niall Ashfield
- Cancer Biotherapeutics Research Group, Life Sciences Institute, School of Biotechnology, Dublin City University, Dublin 9, D09 NR58 Dublin, Ireland; (N.A.); (J.C.)
| | - John Crown
- Cancer Biotherapeutics Research Group, Life Sciences Institute, School of Biotechnology, Dublin City University, Dublin 9, D09 NR58 Dublin, Ireland; (N.A.); (J.C.)
- Department of Medical Oncology, St. Vincent’s University Hospital, Dublin 4, D04 T6F4 Dublin, Ireland
| | - Denis M. Collins
- Cancer Biotherapeutics Research Group, Life Sciences Institute, School of Biotechnology, Dublin City University, Dublin 9, D09 NR58 Dublin, Ireland; (N.A.); (J.C.)
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Nader-Marta G, Singer C, Hlauschek D, DeMichele A, Tarantino P, de Azambuja E, Pfeiler G, Martin M, Balko JM, Nowecki Z, Balic M, Brufsky AM, Chan A, Morris PG, Haddad T, Loibl S, Liu Y, Soelkner L, Fesl C, Mayer EL, Gnant M. Clinical characterization, prognostic, and predictive values of HER2-low in patients with early breast cancer in the PALLAS trial (ABCSG-42/AFT-05/BIG-14-13/PrE0109). Breast Cancer Res 2024; 26:140. [PMID: 39375745 PMCID: PMC11459983 DOI: 10.1186/s13058-024-01899-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 10/01/2024] [Indexed: 10/09/2024] Open
Abstract
BACKGROUND Bidirectional crosstalk between HER2 and estrogen receptor (ER) pathways may influence outcomes and the efficacy of endocrine therapy (ET). Low HER2 expression levels (HER2-low) have emerged as a predictive biomarker in patients with breast cancer (BC). METHODS PALLAS is an open, international, phase 3 study evaluating the addition of palbociclib for 2 years to adjuvant ET in patients with stage II-III ER-positive/HER2-negative BC. To assess the impact of HER2 expression on patient outcomes in the phase III PALLAS trial, we analyzed (1) the association between rate of HER2-low with demographic and clinicopathological parameters, (2) the prognostic value of HER2-low status on invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), and overall survival (OS) and (3) HER2 expression's value as a predictive biomarker of response to palbociclib. HER2-low was defined as HER2 immunohistochemistry (IHC) 1 + or IHC 2 + with negative in situ hybridization (ISH). All pathologic evaluation was performed locally. Prognostic and predictive power of HER2 were assessed with Cox models. RESULTS From the original PALLAS intention-to-treat population (N = 5753), 5304 patients (92.2%) were included in this analysis. Among these, 2254 patients (42.5%) were classified as having HER2 IHC 0 (HER2-0), and 3050 (57.5%) as having HER2-low disease (1838 with IHC 1 + and 1212 with IHC 2 +). Median follow-up was 59.8 months. HER2-low prevalence varied significantly across 21 participating countries (range 16.7% to 75.6%; p < 0.001) and was more frequent in patients enrolled in North America (63.1%) than in Europe (53.4%) or other regions (53.4%) (p < 0.001). HER2 status was not significantly associated with iDFS in a multivariable Cox model (hazard ratio 0.93, 95% confidence interval 0.81 - 1.06). No significant interaction was observed between treatment arm and HER2 status for iDFS (p = 0.43). Similar results were obtained for DRFS and OS. CONCLUSIONS In this large, prospective, global patient cohort, no differences were observed in clinical parameters, prognosis, or differential benefit from palbociclib between HER2-0 and HER2-low tumors. Significant geographic variability was observed in the prevalence of HER2-low status, suggesting a high degree of variation in pathologic assessment of HER2 expression without impact on outcomes.
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Affiliation(s)
- Guilherme Nader-Marta
- Institut Jules Bordet, Academic Trials Promoting Team (ATPT), Université Libre de Bruxelles (U.L.B), Hôpital Universitaire de Bruxelles (HUB), Brussels, Belgium.
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
| | - Christian Singer
- Department of Obstetrics and Gynaecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Dominik Hlauschek
- Austrian Breast and Colorectal Cancer Study Group (ABCSG), Vienna, Austria
| | - Angela DeMichele
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Paolo Tarantino
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Evandro de Azambuja
- Institut Jules Bordet, Academic Trials Promoting Team (ATPT), Université Libre de Bruxelles (U.L.B), Hôpital Universitaire de Bruxelles (HUB), Brussels, Belgium
| | - Georg Pfeiler
- Department of Obstetrics and Gynaecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Miguel Martin
- Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Justin M Balko
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Zbigniew Nowecki
- The Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Marija Balic
- Division of Oncology, Department of Internal Medicine, Medical University Graz, Graz, Austria
- University of Pittsburgh Hillman Cancer Center, Magee-Women's Hospital, Pittsburgh, PA, USA
| | - Adam M Brufsky
- University of Pittsburgh Hillman Cancer Center, Magee-Women's Hospital, Pittsburgh, PA, USA
| | - Arlene Chan
- Breast Cancer Research Centre-WA & Curtin University, Perth, Australia
| | - Patrick G Morris
- Cancer Trials Ireland, Dublin, Ireland
- Beaumont RCSI Cancer Centre, Dublin, Ireland
| | - Tufia Haddad
- Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA
| | - Sibylle Loibl
- German Breast Group, Prof. (Apl), Goethe University Frankfurt, Frankfurt am Main, Germany
- Clinical Consultant Centre for Haematology and Oncology/Bethanien, Frankfurt, Germany
| | - Yuan Liu
- Translational Oncology Global Product Development Pfizer Inc, San Diego, CA, USA
| | - Lidija Soelkner
- Austrian Breast and Colorectal Cancer Study Group (ABCSG), Vienna, Austria
| | - Christian Fesl
- Austrian Breast and Colorectal Cancer Study Group (ABCSG), Vienna, Austria
| | - Erica L Mayer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Michael Gnant
- Austrian Breast and Colorectal Cancer Study Group (ABCSG), Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
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Mondol RK, Millar EKA, Sowmya A, Meijering E. BioFusionNet: Deep Learning-Based Survival Risk Stratification in ER+ Breast Cancer Through Multifeature and Multimodal Data Fusion. IEEE J Biomed Health Inform 2024; 28:5290-5302. [PMID: 38913518 DOI: 10.1109/jbhi.2024.3418341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Breast cancer is a significant health concern affecting millions of women worldwide. Accurate survival risk stratification plays a crucial role in guiding personalised treatment decisions and improving patient outcomes. Here we present BioFusionNet, a deep learning framework that fuses image-derived features with genetic and clinical data to obtain a holistic profile and achieve survival risk stratification of ER+ breast cancer patients. We employ multiple self-supervised feature extractors (DINO and MoCoV3) pretrained on histopathological patches to capture detailed image features. These features are then fused by a variational autoencoder and fed to a self-attention network generating patient-level features. A co-dual-cross-attention mechanism combines the histopathological features with genetic data, enabling the model to capture the interplay between them. Additionally, clinical data is incorporated using a feed-forward network, further enhancing predictive performance and achieving comprehensive multimodal feature integration. Furthermore, we introduce a weighted Cox loss function, specifically designed to handle imbalanced survival data, which is a common challenge. Our model achieves a mean concordance index of 0.77 and a time-dependent area under the curve of 0.84, outperforming state-of-the-art methods. It predicts risk (high versus low) with prognostic significance for overall survival in univariate analysis (HR=2.99, 95% CI: 1.88-4.78, p 0.005), and maintains independent significance in multivariate analysis incorporating standard clinicopathological variables (HR=2.91, 95% CI: 1.80-4.68, p 0.005).
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Kadamkulam Syriac A, Nandu NS, Clark A, Tavallai M, Jin DX, Sokol E, McGregor K, Ross JS, Danziger N, Leone JP. Genomic profiling and comparative analysis of male versus female metastatic breast cancer across subtypes. Breast Cancer Res 2024; 26:118. [PMID: 39049124 PMCID: PMC11267671 DOI: 10.1186/s13058-024-01872-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 07/15/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND Male breast cancer (MaBC) has limited data on genomic alterations. We aimed to comprehensively describe and compare MaBC's genomics with female breast cancer's (FBC) across subtypes. METHODS Using genomic data from Foundation Medicine, we categorized 253 MaBC into estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative (n = 210), ER-positive/HER2-positive (n = 22) and triple-negative (n = 20). One ER-negative/HER2-positive case was excluded due to n-of-1. The genomics of the final MaBC cohort (n = 252) were compared to a FBC cohort (n = 2708) stratified by molecular subtype, with adjusted p-values. In the overall MaBC and FBC cohorts, we compared mutational prevalence in cancer susceptibility genes (CSG) (ATM/BRCA1/BRCA2/CHEK2/PALB2). RESULTS Comparing ER-positive/HER2-negative cases, MaBc had increased alterations in GATA3 (26.2% vs. 15.9%, p = 0.005), BRCA2 (13.8% vs. 5.3%, p < 0.001), MDM2 (13.3% vs. 6.14%, p = 0.004) and CDK4 (7.1% vs. 1.8%, p < 0.001); and decreased frequency of TP53 (11.0% vs. 42.6%, p < 0.001) and ESR1 mutations (5.7% vs. 14.6%, p < 0.001). Comparing ER-positive/HER2-positive cases, MaBC had increased short variants in ERBB2 (22.7% vs. 0.6%, p = 0.002), GATA3 (36.3% vs. 6.2%, p = 0.004), and MDM2 (36.3% vs. 4.9%, p = 0.002); decreased frequency of TP53 alterations was seen in MaBC versus FBC (9.1% vs. 61.7%, p < 0.001). Within triple-negative cases, MaBC had decreased alterations in TP53 compared to FBC (25.0% vs. 84.4%, p < 0.001). MaBC had higher frequency of CSG variants than FBC (22.6% vs. 14.6%, p < 0.05), with increased BRCA mutations in MaBC (14.6% vs. 9.1%, p < 0.05). CONCLUSIONS Although MaBC and FBC share some common alterations, our study revealed several important differences relevant to tumor biology and implications for targeted therapies.
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Affiliation(s)
- Arun Kadamkulam Syriac
- Dana-Farber Cancer Institute at St. Elizabeth's Medical Center, Boston, MA, USA
- Mass General Cancer Center at Wentworth-Douglass Hospital, Dover, NH, USA
| | - Nitish Singh Nandu
- University Hospital, University of Missouri Health Care, Columbia, MO, USA
| | | | | | | | | | | | - Jeffrey S Ross
- Foundation Medicine, Cambridge, MA, USA
- Upstate Medical University, Syracuse, NY, USA
| | | | - Jose Pablo Leone
- Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA.
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
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Yang C, Wu L, Jin X, Liu A, Jing Z, Feng C, Guo Z, Zhang Y, Ma Y, Li F, Wen Z, Yan L, Yang Y, Ji X, Zhang Y. Decrease in GPSM2 mediated by the natural product luteolin contributes to colon adenocarcinoma treatment and increases the sensitivity to fluorouracil. Biomed Pharmacother 2024; 176:116847. [PMID: 38823277 DOI: 10.1016/j.biopha.2024.116847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 05/22/2024] [Accepted: 05/27/2024] [Indexed: 06/03/2024] Open
Abstract
Luteolin, a monomeric substance, is a natural product of the Brucea javanica (BJ) plant. Brucea javanica oil emulsion injection (BJOEI) is a proprietary Chinese medicine purified from BJ that is widely used clinically as an anti-tumor treatment. Although a growing body of research suggests that luteolin and BJOEI have anti-tumor effects, the molecular mechanism of action has not been fully elucidated. In this study, through molecular docking technology, we found that luteolin can interact directly with GPSM2 and regulate the FoxO signaling pathway through GPSM2. In addition, the inhibitory effect of luteolin on colon adenocarcinoma (COAD) cells was found to be offset by knockdown of GPSM2. In contrast, the anti-proliferative effects of luteolin could be notably reversed by overexpression of GPSM2. The results reveal that GPSM2 is crucial in luteolin-mediated anti-proliferative effects. The mediation of anti-proliferative effects by GPSM2 has also been indirectly demonstrated in RKO and SW480 xenograft mice models. In addition, we verified that BJOEI inhibits the progression of COAD by mediating GPSM2 and regulating the FoxO signaling pathway. We also found that BJOEI achieved a better anti-tumor effect when combined with fluorouracil injection. Collectively, our data show that the anti-tumor effects of BJOEI and luteolin on COAD are GPSM2-dependent and downregulating the expression of GPSM2 to regulate the FoxO signaling pathway may be an effective way to treat COAD.
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Affiliation(s)
- Chunjiao Yang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China; Department of Oncology, The Fifth Affiliated Hospital of Guangxi Medical University & The First People's Hospital of Nanning, Nanning, Guangxi, China
| | - Lina Wu
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
| | - Xin Jin
- Department of Respiratory Medicine, The Fifth Affiliated Hospital of Guangxi Medical University & The First People's Hospital of Nanning, Nanning, Guangxi, China
| | - Aoran Liu
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China
| | - Zhitao Jing
- The First Hospital of China Medical University, Shenyang, China
| | - Chuhan Feng
- Liaoning University Of Traditional Chinese Medicine, Shenyang, China
| | - Zhengting Guo
- The First Clinical College, China Medical University, Shenyang, China
| | - Yuzhe Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China
| | - Yanju Ma
- Department of Medical Oncology, Cancer Hospital of China Medical University, China
| | - Fang Li
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China
| | - Zhenpeng Wen
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China; Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Lirong Yan
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China
| | - Yi Yang
- Department of Laboratory Animal Science, China Medical University, Shenyang, China
| | - Xu Ji
- The First Hospital of China Medical University, Shenyang, China.
| | - Ye Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China.
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Pan L, Li J, Xu Q, Gao Z, Yang M, Wu X, Li X. HER2/PI3K/AKT pathway in HER2-positive breast cancer: A review. Medicine (Baltimore) 2024; 103:e38508. [PMID: 38875362 PMCID: PMC11175886 DOI: 10.1097/md.0000000000038508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/01/2024] [Accepted: 05/17/2024] [Indexed: 06/16/2024] Open
Abstract
Breast cancer is currently the most commonly occurring cancer globally. Among breast cancer cases, the human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for 15% to 20% and is a crucial focus in the treatment of breast cancer. Common HER2-targeted drugs approved for treating early and/or advanced breast cancer include trastuzumab and pertuzumab, which effectively improve patient prognosis. However, despite treatment, most patients with terminal HER2-positive breast cancer ultimately suffer death from the disease due to primary or acquired drug resistance. The prevalence of aberrantly activated the protein kinase B (AKT) signaling in HER2-positive breast cancer was already observed in previous studies. It is well known that p-AKT expression is linked to an unfavorable prognosis, and the phosphatidylinositol-3-kinase (PI3K)/AKT pathway, as the most common mutated pathway in breast cancer, plays a major role in the mechanism of drug resistance. Therefore, in the current review, we summarize the molecular alterations present in HER2-positive breast cancer, elucidate the relationships between HER2 overexpression and alterations in the PI3K/AKT signaling pathway and the pathways of the alterations in breast cancer, and summarize the resistant mechanism of drugs targeting the HER2-AKT pathway, which will provide an adjunctive therapeutic rationale for subsequent resistance to directed therapy in the future.
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Affiliation(s)
- Linghui Pan
- Institute for Cancer Medicine and School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Jinling Li
- Institute for Cancer Medicine and School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
- Department of Laboratory Medicine, Chonggang General Hospital, Chongqing, China
| | - Qi Xu
- Institute for Cancer Medicine and School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Zili Gao
- Institute for Cancer Medicine and School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Mao Yang
- Institute for Cancer Medicine and School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Xiaoping Wu
- Institute for Cancer Medicine and School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Xuesen Li
- Institute for Cancer Medicine and School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
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Kutlu Y, Cekin R, Aydin SG, Shbair ATM, Bilici A, Arici S, Oven BB, Acikgoz O, Ozcan E, Olmez OF, Cakir A, Seker M. Prognostic significance of HER2 loss after HER2-targeted neoadjuvant treatment in patients with HER2-positive locally advanced breast cancer. Curr Probl Cancer 2024; 50:101102. [PMID: 38735211 DOI: 10.1016/j.currproblcancer.2024.101102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 04/21/2024] [Accepted: 04/25/2024] [Indexed: 05/14/2024]
Abstract
Loss of human epidermal growth factor receptor 2 (HER2) expression can be seen in almost 25-30 % patients after HER2 receptor directed neoadjuvant treatment. These patients have unclear clinical outcomes in previous studies. We aimed to investigate the importance of HER2 loss, additionally with predictive factors for the loss of HER2. This was a retrospective and multicenter study that included 272 HER2-positive BC patients with no pathological complete response who received neoadjuvant chemotherapy plus HER2-targeted treatments. The factors that may affect the loss of HER2 detected by immunohistochemistry(IHC) and the association with survival were analyzed.The rate of HER2 loss after neoadjuvant treatments(NAT) was 27.9 % (n = 76). Disease recurrence was observed in 18(23.7 %) patients with HER2 loss, while it was detected in 62 (31.7 %) patients without HER2 loss(p = 0.23). Pre and post-NAT ER status, and post-NAT ki-67 status had a significant impact on disease-free survival(DFS) (p = 0.0012, p = 0.004, and p = 0.04, respectively).There were no significant association between DFS and loss of HER2 (p = 0.64) and dual anti-HER2 blockade (p = 0.21). Pre-NAT clinical stage (HR:1.65 p = 0.013), post-NAT LN status (HR:3.18, p = 0.02) and pre-NAT ER status (HR:0.24, p = 0.041) were significant independent prognostic factors for DFS while post-NAT residual disease in axillar tissue was an independent prognostic factor for OS (HR:1.54 p = 0.019). Moreover, age (<40 years vs ≥40 years) (p = 0.031) and tumor grade (p = 0.004) were predictive factors for HER2 loss. Our results showed that HER2 loss did not affect survivals. However, young age and being high grade tumor may predict HER2 loss.
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Affiliation(s)
- Yasin Kutlu
- Department of Medical Oncology, Medipol University Faculty of Medicine, Istanbul, Turkey.
| | - Ruhper Cekin
- Department of Medical Oncology, Prof. Dr. Cemil Tascioglu City Hospital, Istanbul, Turkey
| | - Sabin Goktas Aydin
- Department of Medical Oncology, Medipol University Faculty of Medicine, Istanbul, Turkey
| | - Abdallah T M Shbair
- Department of Medical Oncology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Ahmet Bilici
- Department of Medical Oncology, Medipol University Faculty of Medicine, Istanbul, Turkey
| | - Serdar Arici
- Department of Medical Oncology, Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Bala Basak Oven
- Department of Medical Oncology, Yeditepe University Faculty of Medicine, Istanbul, Turkey
| | - Ozgur Acikgoz
- Department of Medical Oncology, Medipol University Faculty of Medicine, Istanbul, Turkey
| | - Erkan Ozcan
- Department of Medical Oncology, Trakya University Faculty of Medicine, Istanbul, Turkey
| | - Omer Fatih Olmez
- Department of Medical Oncology, Medipol University Faculty of Medicine, Istanbul, Turkey
| | - Asli Cakir
- Department of Pathology, Medipol University Faculty of Medicine, Istanbul, Turkey
| | - Mesut Seker
- Department of Medical Oncology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
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8
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Marra A, Chandarlapaty S, Modi S. Management of patients with advanced-stage HER2-positive breast cancer: current evidence and future perspectives. Nat Rev Clin Oncol 2024; 21:185-202. [PMID: 38191924 DOI: 10.1038/s41571-023-00849-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/11/2023] [Indexed: 01/10/2024]
Abstract
Amplification and/or overexpression of ERBB2, the gene encoding HER2, can be found in 15-20% of invasive breast cancers and is associated with an aggressive phenotype and poor clinical outcomes. Relentless research efforts in molecular biology and drug development have led to the implementation of several HER2-targeted therapies, including monoclonal antibodies, tyrosine-kinase inhibitors and antibody-drug conjugates, constituting one of the best examples of bench-to-bedside translation in oncology. Each individual drug class has improved patient outcomes and, importantly, the combinatorial and sequential use of different HER2-targeted therapies has increased cure rates in the early stage disease setting and substantially prolonged survival for patients with advanced-stage disease. In this Review, we describe key steps in the development of the modern paradigm for the treatment of HER2-positive advanced-stage breast cancer, including selecting and sequencing new-generation HER2-targeted therapies, and summarize efficacy and safety outcomes from pivotal studies. We then outline the factors that are currently known to be related to resistance to HER2-targeted therapies, such as HER2 intratumoural heterogeneity, activation of alternative signalling pathways and immune escape mechanisms, as well as potential strategies that might be used in the future to overcome this resistance and further improve patient outcomes.
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Affiliation(s)
- Antonio Marra
- Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy
| | - Sarat Chandarlapaty
- Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Shanu Modi
- Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Weill Cornell Medical College, New York, NY, USA.
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9
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Liang Y, Liu X, Yun Z, Li K, Li H. Endocrine therapy plus HER2-targeted therapy, another favorable option for HR+/HER2+ advanced breast cancer patients. Ther Adv Med Oncol 2024; 16:17588359231220501. [PMID: 38188468 PMCID: PMC10771751 DOI: 10.1177/17588359231220501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 11/21/2023] [Indexed: 01/09/2024] Open
Abstract
Advanced breast cancer (ABC) that is positive for hormone receptors (HRs) and human epidermal growth factor receptor 2 (HER2) is a cancer subtype with distinctive characteristics. The primary treatment guidelines suggest that a combination therapy comprising anti-HER2 therapy and chemotherapy should be administered as the initial treatment for HR-positive/ HER2-positive (HR+/HER2+) ABC. However, crosstalk between the HR and HER2 pathways can partially account for the resistance of HR+/HER2+ disease to HER2-targeted therapy. This, in turn, provides a rationale for the concomitant administration of HER2-targeted therapy and endocrine therapy (ET). Many clinical studies have confirmed that the combination of HER2-targeted therapy and ET as a first-line treatment is not inferior to the combination of HER2-targeted therapy and chemotherapy, and support its use as a first-line treatment choice for HR+/HER2+ ABC. Other drugs, such as antibody-drug conjugates, cyclin-dependent kinase 4/6 inhibitors, phosphatidylinositol 3-kinase-protein kinase B (AKT)-mammalian target of rapamycin inhibitors, and programmed cell death protein 1 or programmed cell death ligand 1 inhibitors, may also improve the prognosis of patients with breast cancer by blocking signaling pathways associated with tumor proliferation and break new ground for the treatment of HR+/HER2+ ABC.
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Affiliation(s)
- Yuehua Liang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiaoran Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Zehui Yun
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Kun Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Huiping Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
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10
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López-Méndez JA, Ventura-Gallegos JL, Camacho-Arroyo I, Lizano M, Cabrera-Quintero AJ, Romero-Córdoba SL, Martínez-Vázquez M, Jacobo-Herrera NJ, León-Del-Río A, Paredes-Villa AA, Zentella-Dehesa A. The inhibitory effect of trastuzumab on BT474 triple‑positive breast cancer cell viability is reversed by the combination of progesterone and estradiol. Oncol Lett 2024; 27:19. [PMID: 38034484 PMCID: PMC10688505 DOI: 10.3892/ol.2023.14152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 10/10/2023] [Indexed: 12/02/2023] Open
Abstract
Breast cancer expressing the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) is known as triple-positive (TPBC). TPBC represents 9-11% of breast cancer cases worldwide and is a heterogeneous subtype. Notably, TPBC presents a therapeutic challenge due to the crosstalk between the hormonal (ER and PR) and HER2 pathways. Patients with TPBC are treated with trastuzumab (TTZ); however, several patients treated with TTZ tend to relapse. The present study aimed to investigate the effect of the PR on inhibitory effect of TTZ on cell viability. BT474 cells (a model of TPBC) and BT474 PR-silenced cells were treated with either TTZ, progesterone (Pg), the PR antagonist mifepristone (RU486) or estradiol (E2) alone or in combination for 144 h (6 days). Cell viability assays and western blotting were subsequently performed. The results showed that Pg and E2 interfered with the inhibitory effect of TTZ on cell viability and this effect was potentiated when both hormones were combined. Pg was revealed to act through the PR, mainly activating the PR isoform B (PR-B) and inducing the protein expression levels of CDK4 and cyclin D1; however, it did not reactivate the HER2/Akt pathway. By contrast, E2 was able to increase PR isoform A (PR-A) expression, which was inhibited by Pg. Notably, in most of the experiments, RU486 did not antagonize the effects of Pg. In conclusion, Pg and E2 may interfere with the inhibitory effect of TTZ on cell viability through PR-B activation and PR-A inactivation.
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Affiliation(s)
- José A. López-Méndez
- Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
- Unidad de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 14000 Mexico City, Mexico
| | - José L. Ventura-Gallegos
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
- Unidad de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 14000 Mexico City, Mexico
- Programa Institucional de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
| | - Ignacio Camacho-Arroyo
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología-Facultad de Química, Universidad Nacional Autónoma de México, 11000 Mexico City, Mexico
| | - Marcela Lizano
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico
| | - Alberto J. Cabrera-Quintero
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
- Unidad de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 14000 Mexico City, Mexico
| | - Sandra L. Romero-Córdoba
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
- Unidad de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 14000 Mexico City, Mexico
- Programa Institucional de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
| | - Mariano Martínez-Vázquez
- Departamento de Productos Naturales, Instituto de Química, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
| | - Nadia J. Jacobo-Herrera
- Unidad de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 14000 Mexico City, Mexico
| | - Alfonso León-Del-Río
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
- Programa Institucional de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
| | - Adrian A. Paredes-Villa
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
| | - Alejandro Zentella-Dehesa
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
- Unidad de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 14000 Mexico City, Mexico
- Programa Institucional de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
- Red de Apoyo a la Investigación, Universidad Nacional Autónoma de México-Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 14000 Mexico City, Mexico
- Cancer Center, American British Cowdray Medical Center, 01120 Mexico City, Mexico
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11
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Pegram M, Pietras R, Dang CT, Murthy R, Bachelot T, Janni W, Sharma P, Hamilton E, Saura C. Evolving perspectives on the treatment of HR+/HER2+ metastatic breast cancer. Ther Adv Med Oncol 2023; 15:17588359231187201. [PMID: 37576607 PMCID: PMC10422890 DOI: 10.1177/17588359231187201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 06/21/2023] [Indexed: 08/15/2023] Open
Abstract
Breast cancer (BC) with expression of the estrogen receptor (ER) and/or progesterone receptor (PR) protein and with overexpression/amplification of the human epidermal growth factor receptor 2 (HER2), termed hormone receptor-positive (HR+)/HER2+ BC, represents ∼10% of all BCs in the United States. HR+/HER2+ BC includes HER2+ BCs that are ER+, PR+, or both ER+ and PR+ (triple-positive BC). Although the current guideline-recommended treatment combination of anti-HER2 monoclonal antibodies plus chemotherapy is an effective first-line therapy for many patients with HER2+ advanced disease, intratumoral heterogeneity within the HR+/HER2+ subtype and differences between the HR+/HER2+ subtype and the HR-/HER2+ subtype suggest that other targeted combinations could be investigated in randomized clinical trials for patients with HR+/HER2+ BC. In addition, published data indicate that crosstalk between HRs and HER2 can lead to treatment resistance. Dual HR and HER2 pathway targeting has been shown to be a rational approach to effective and well-tolerated therapy for patients with tumors driven by HER2 and HR, as it may prevent development of resistance by blocking receptor pathway crosstalk. However, clinical trial data for such approaches are limited. Treatments to attenuate other signaling pathways involved in receptor crosstalk are also under investigation for inclusion in dual receptor targeting regimens. These include cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, based on the rationale that association of CDK4/6 with cyclin D1 may play a role in resistance to HER2-directed therapies, and others such as phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway inhibitors. Herein, we will review the scientific and clinical rationale for combined receptor blockade targeting HER2 and ER for patients with advanced-stage HR+/HER2+ disease.
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Affiliation(s)
- Mark Pegram
- Stanford Comprehensive Cancer Institute, Stanford University School of Medicine, Lorry Lokey Building/SIM 1, 265 Campus Drive, Ste G2103, Stanford, CA 94305-5456, USA
| | - Richard Pietras
- Division of Hematology-Oncology, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA
| | - Chau T. Dang
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Rashmi Murthy
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Thomas Bachelot
- Department of Medical Oncology, Centre Léon Bérard, Lyon, France
| | - Wolfgang Janni
- Department of Gynecology and Obstetrics, University Hospital Ulm, University of Ulm, Ulm, Germany
| | - Priyanka Sharma
- Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Erika Hamilton
- Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA
| | - Cristina Saura
- Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), Medical Oncology Service, Barcelona, Spain
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12
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Qiu J, Liu Q, Li P, Jiang Q, Chen W, Li D, Li G, Shan G. Ligand-Directed Photodegradation of Interacting Proteins: Oxidative HER2/HER3 Heterodimer Degradation with a Lapatinib-Derived Photosensitizer. J Med Chem 2023; 66:10265-10272. [PMID: 37421416 DOI: 10.1021/acs.jmedchem.3c00252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/10/2023]
Abstract
In this work, we described a photocatalytic approach, termed ligand-directed photodegradation of interacting proteins (LDPIP), for efficient protein-protein heterodimer degradation. This LDPIP approach utilizes a combination of a photosensitizing protein ligand and appropriate light and molecular oxygen to induce oxidative damage to the ligand-binding protein as well as its interacting protein partner. As a showcase study, a photosensitizing HER2 ligand HER-PS-I was rationally designed based on the FDA-approved HER2 inhibitor lapatinib to efficiently degrade HER2 together with its interacting protein partner HER3, which is thought to induce HER2-targeted therapy resistance and difficult to target by small molecules. HER-PS-I exhibited excellent anticancer activity against drug-resistant MDA-MB-453 cells and its three-dimensional multicellular spheroids. We hope that this LDPIP approach would find more applications in degrading proteins that are thought undruggable or difficult to drug.
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Affiliation(s)
- Jingru Qiu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, P. R. China
| | - Qinghong Liu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, P. R. China
| | - Peixia Li
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, P. R. China
| | - Qiaoyun Jiang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, P. R. China
| | - Weijia Chen
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, P. R. China
| | - Donghai Li
- Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China
| | - Guiling Li
- Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China
| | - Gang Shan
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, P. R. China
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13
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Sadaf, Hazazi A, Alkhalil SS, Alsaiari AA, Gharib AF, Alhuthali HM, Rana S, Aloliqi AA, Eisa AA, Hasan MR, Dev K. Role of Fork-Head Box Genes in Breast Cancer: From Drug Resistance to Therapeutic Targets. Biomedicines 2023; 11:2159. [PMID: 37626655 PMCID: PMC10452497 DOI: 10.3390/biomedicines11082159] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 07/17/2023] [Accepted: 07/25/2023] [Indexed: 08/27/2023] Open
Abstract
Breast cancer has been acknowledged as one of the most notorious cancers, responsible for millions of deaths around the globe. Understanding the various factors, genetic mutations, comprehensive pathways, etc., that are involved in the development of breast cancer and how these affect the development of the disease is very important for improving and revitalizing the treatment of this global health issue. The forkhead-box gene family, comprising 19 subfamilies, is known to have a significant impact on the growth and progression of this cancer. The article looks into the various forkhead genes and how they play a role in different types of cancer. It also covers their impact on cancer drug resistance, interaction with microRNAs, explores their potential as targets for drug therapies, and their association with stem cells.
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Affiliation(s)
- Sadaf
- Department of Biotechnology, Jamia Millia Islamia, New Delhi 110025, India;
| | - Ali Hazazi
- Department of Pathology and Laboratory Medicine, Security Forces Hospital Program, Riyadh 11481, Saudi Arabia;
| | - Samia S. Alkhalil
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Alquwayiyah 11961, Saudi Arabia;
| | - Ahad Amer Alsaiari
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia; (A.A.A.); (A.F.G.); (H.M.A.)
| | - Amal F. Gharib
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia; (A.A.A.); (A.F.G.); (H.M.A.)
| | - Hayaa M. Alhuthali
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia; (A.A.A.); (A.F.G.); (H.M.A.)
| | - Shanika Rana
- School of Biosciences, Apeejay Stya University, Gurugram 122003, India;
| | - Abdulaziz A. Aloliqi
- Department of Medical Biotechnology, College of Applied Medical Sciences, Qassim University, Buraydah 52571, Saudi Arabia;
| | - Alaa Abdulaziz Eisa
- Department of Medical Laboratories Technology, College of Applied Medical Sciences, Taibah University, Medina 30002, Saudi Arabia;
| | - Mohammad Raghibul Hasan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Alquwayiyah 11961, Saudi Arabia;
| | - Kapil Dev
- Department of Biotechnology, Jamia Millia Islamia, New Delhi 110025, India;
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14
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Pegram M, Jackisch C, Johnston SRD. Estrogen/HER2 receptor crosstalk in breast cancer: combination therapies to improve outcomes for patients with hormone receptor-positive/HER2-positive breast cancer. NPJ Breast Cancer 2023; 9:45. [PMID: 37258523 DOI: 10.1038/s41523-023-00533-2] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 04/04/2023] [Indexed: 06/02/2023] Open
Abstract
The human epidermal growth factor receptor 2 (HER2) is overexpressed in 13-22% of breast cancers (BC). Approximately 60-70% of HER2+ BC co-express hormone receptors (HRs). HR/HER2 co-expression modulates response to both anti-HER2-directed and endocrine therapy due to "crosstalk" between the estrogen receptor (ER) and HER2 pathways. Combined HER2/ER blockade may be an effective treatment strategy for patients with HR+/HER2+ BC in the appropriate clinical setting(s). In this review, we provide an overview of crosstalk between the ER and HER2 pathways, summarize data from recently published and ongoing clinical trials, and discuss clinical implications for targeted treatment of HR+/HER2+ BC.
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Affiliation(s)
- Mark Pegram
- Stanford Cancer Institute, Stanford, CA, USA.
| | - Christian Jackisch
- Obstetrics and Gynaecology and Breast Cancer Center, Klinikum Offenbach GmbH, Offenbach, Germany
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15
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Swain SM, Shastry M, Hamilton E. Targeting HER2-positive breast cancer: advances and future directions. Nat Rev Drug Discov 2023; 22:101-126. [PMID: 36344672 PMCID: PMC9640784 DOI: 10.1038/s41573-022-00579-0] [Citation(s) in RCA: 451] [Impact Index Per Article: 225.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2022] [Indexed: 11/09/2022]
Abstract
The long-sought discovery of HER2 as an actionable and highly sensitive therapeutic target was a major breakthrough for the treatment of highly aggressive HER2-positive breast cancer, leading to approval of the first HER2-targeted drug - the monoclonal antibody trastuzumab - almost 25 years ago. Since then, progress has been swift and the impressive clinical activity across multiple trials with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates that target HER2 has spawned extensive efforts to develop newer platforms and more targeted therapies. This Review discusses the current standards of care for HER2-positive breast cancer, mechanisms of resistance to HER2-targeted therapy and new therapeutic approaches and agents, including strategies to harness the immune system.
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Affiliation(s)
- Sandra M Swain
- Department of Medicine, Georgetown Lombardi Comprehensive Cancer Center and MedStar Health, Washington, DC, USA.
| | | | - Erika Hamilton
- Sarah Cannon Research Institute, Nashville, TN, USA
- Tennessee Oncology, Nashville, TN, USA
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16
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Mathur R, Jha NK, Saini G, Jha SK, Shukla SP, Filipejová Z, Kesari KK, Iqbal D, Nand P, Upadhye VJ, Jha AK, Roychoudhury S, Slama P. Epigenetic factors in breast cancer therapy. Front Genet 2022; 13:886487. [PMID: 36212140 PMCID: PMC9539821 DOI: 10.3389/fgene.2022.886487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 07/20/2022] [Indexed: 11/17/2022] Open
Abstract
Epigenetic modifications are inherited differences in cellular phenotypes, such as cell gene expression alterations, that occur during somatic cell divisions (also, in rare circumstances, in germ line transmission), but no alterations to the DNA sequence are involved. Histone alterations, polycomb/trithorax associated proteins, short non-coding or short RNAs, long non—coding RNAs (lncRNAs), & DNA methylation are just a few biological processes involved in epigenetic events. These various modifications are intricately linked. The transcriptional potential of genes is closely conditioned by epigenetic control, which is crucial in normal growth and development. Epigenetic mechanisms transmit genomic adaptation to an environment, resulting in a specific phenotype. The purpose of this systematic review is to glance at the roles of Estrogen signalling, polycomb/trithorax associated proteins, DNA methylation in breast cancer progression, as well as epigenetic mechanisms in breast cancer therapy, with an emphasis on functionality, regulatory factors, therapeutic value, and future challenges.
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Affiliation(s)
- Runjhun Mathur
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
- Dr. A.P.J Abdul Kalam Technical University, Lucknow, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
- Department of Biotechnology, School of Applied and Life Sciences (SALS), Uttaranchal University, Dehradun, India
- Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, India
| | - Gaurav Saini
- Department of Civil Engineering, Netaji Subhas University of Technology, Delhi, India
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
- Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, India
| | - Sheo Prasad Shukla
- Department of Civil Engineering, Rajkiya Engineering College, Banda, India
| | - Zita Filipejová
- Small Animal Clinic, University of Veterinary Sciences Brno, Brno, Czechia
| | | | - Danish Iqbal
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majma'ah, Saudi Arabia
- Health and Basic Sciences Research Center, Majmaah University, Al Majma'ah, Saudi Arabia
| | - Parma Nand
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
| | - Vijay Jagdish Upadhye
- Center of Research for Development (CR4D), Parul Institute of Applied Sciences (PIAS), Parul University, Vadodara, Gujarat
| | - Abhimanyu Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
- *Correspondence: Abhimanyu Kumar Jha, ; Shubhadeep Roychoudhury,
| | - Shubhadeep Roychoudhury
- Department of Life Science and Bioinformatics, Assam University, Silchar, India
- *Correspondence: Abhimanyu Kumar Jha, ; Shubhadeep Roychoudhury,
| | - Petr Slama
- Department of Animal Morphology, Physiology, and Genetics, Faculty of AgriSciences, Mendel University in Brno, Brno, Czechia
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17
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Gámez-Chiachio M, Sarrió D, Moreno-Bueno G. Novel Therapies and Strategies to Overcome Resistance to Anti-HER2-Targeted Drugs. Cancers (Basel) 2022; 14:4543. [PMID: 36139701 PMCID: PMC9496705 DOI: 10.3390/cancers14184543] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/09/2022] [Accepted: 09/15/2022] [Indexed: 11/17/2022] Open
Abstract
The prognosis and quality of life of HER2 breast cancer patients have significantly improved due to the crucial clinical benefit of various anti-HER2 targeted therapies. However, HER2 tumors can possess or develop several resistance mechanisms to these treatments, thus leaving patients with a limited set of additional therapeutic options. Fortunately, to overcome this problem, in recent years, multiple different and complementary approaches have been developed (such as antibody-drug conjugates (ADCs)) that are in clinical or preclinical stages. In this review, we focus on emerging strategies other than on ADCs that are either aimed at directly target the HER2 receptor (i.e., novel tyrosine kinase inhibitors) or subsequent intracellular signaling (e.g., PI3K/AKT/mTOR, CDK4/6 inhibitors, etc.), as well as on innovative approaches designed to attack other potential tumor weaknesses (such as immunotherapy, autophagy blockade, or targeting of other genes within the HER2 amplicon). Moreover, relevant technical advances such as anti-HER2 nanotherapies and immunotoxins are also discussed. In brief, this review summarizes the impact of novel therapeutic approaches on current and future clinical management of aggressive HER2 breast tumors.
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Affiliation(s)
- Manuel Gámez-Chiachio
- Biochemistry Department, Medicine Faculty, Universidad Autónoma Madrid-CSIC, IdiPaz, 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red-Oncología (CIBERONC), 28029 Madrid, Spain
| | - David Sarrió
- Biochemistry Department, Medicine Faculty, Universidad Autónoma Madrid-CSIC, IdiPaz, 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red-Oncología (CIBERONC), 28029 Madrid, Spain
| | - Gema Moreno-Bueno
- Biochemistry Department, Medicine Faculty, Universidad Autónoma Madrid-CSIC, IdiPaz, 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red-Oncología (CIBERONC), 28029 Madrid, Spain
- MD Anderson International Foundation, 28033 Madrid, Spain
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18
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Majorini MT, Colombo MP, Lecis D. Few, but Efficient: The Role of Mast Cells in Breast Cancer and Other Solid Tumors. Cancer Res 2022; 82:1439-1447. [PMID: 35045983 PMCID: PMC9306341 DOI: 10.1158/0008-5472.can-21-3424] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/17/2021] [Accepted: 01/13/2022] [Indexed: 01/07/2023]
Abstract
Tumor outcome is determined not only by cancer cell-intrinsic features but also by the interaction between cancer cells and their microenvironment. There is great interest in tumor-infiltrating immune cells, yet mast cells have been less studied. Recent work has highlighted the impact of mast cells on the features and aggressiveness of cancer cells, but the eventual effect of mast cell infiltration is still controversial. Here, we review multifaceted findings regarding the role of mast cells in cancer, with a particular focus on breast cancer, which is further complicated because of its classification into subtypes characterized by different biological features, outcome, and therapeutic strategies.
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Affiliation(s)
| | - Mario Paolo Colombo
- Corresponding Authors: Daniele Lecis, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, Milano 20133, Italy. Phone: 022-390-2212; E-mail: ; and Mario Paolo Colombo,
| | - Daniele Lecis
- Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.,Corresponding Authors: Daniele Lecis, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, Milano 20133, Italy. Phone: 022-390-2212; E-mail: ; and Mario Paolo Colombo,
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19
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Salkeni MA, Rizvi W, Hein K, Higa GM. Neu Perspectives, Therapies, and Challenges for Metastatic HER2-Positive Breast Cancer. BREAST CANCER-TARGETS AND THERAPY 2021; 13:539-557. [PMID: 34602823 PMCID: PMC8481821 DOI: 10.2147/bctt.s288344] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 08/20/2021] [Indexed: 12/26/2022]
Abstract
Even though gene amplification or protein overexpression occurs in approximately one-fifth of all breast cancers, the discovery of HER2 has, nevertheless, had profound implications for the disease. Indeed, the characterization of the receptor resulted in a number of significant advances. Structurally, unique features provided avenues for the development of numerous compounds with target-specificity; molecularly, biological constructs revealed a highly complex, internal signal transduction pathway with regulatory effects on tumor proliferation, survival, and perhaps, even resistance; and clinically, disease outcomes manifested its predictive and prognostic value. Yet despite the receptor’s utility, the beneficial effects are diminished by tumor recurrence after neo- or adjuvant therapy as well as losses resulting from the inability to cure patients with metastatic disease. What these observations suggest is that while tumor response may be partially linked to uncoupling cell surface message reception and nuclear gene expression, as well as recruitment of the innate immune system, disease progression and/or resistance may involve a reprogrammable signaling mainframe that elicits alternative growth and survival signals. This review attempts to meld current perceptions related to HER2-positive metastatic breast cancer with particular attention to current biological insights and therapeutic challenges.
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Affiliation(s)
- Mohamad Adham Salkeni
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Wajeeha Rizvi
- Department of Internal Medicine, West Virginia University, Morgantown, WV, USA
| | - Kyaw Hein
- Department of Business, Lamar University, Houston, TX, USA
| | - Gerald M Higa
- Departments of Clinical Pharmacy and Medicine, West Virginia University, Morgantown, WV, USA
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20
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Huynh TK, Huang CH, Chen JY, Yao JH, Yang YS, Wei YL, Chen HF, Chen CH, Tu CY, Hsu YM, Liu LC, Huang WC. MiR-221 confers lapatinib resistance by negatively regulating p27 kip1 in HER2-positive breast cancer. Cancer Sci 2021; 112:4234-4245. [PMID: 34382727 PMCID: PMC8486195 DOI: 10.1111/cas.15107] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 08/02/2021] [Accepted: 08/09/2021] [Indexed: 12/02/2022] Open
Abstract
Development of acquired resistance to lapatinib, a dual epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor, severely limits the duration of clinical response in advanced HER2‐driven breast cancer patients. Although the compensatory activation of the PI3K/Akt survival signal has been proposed to cause acquired lapatinib resistance, comprehensive molecular mechanisms remain required to develop more efficient strategies to circumvent this therapeutic difficulty. In this study, we found that suppression of HER2 by lapatinib still led to Akt inactivation and elevation of FOX3a protein levels, but failed to induce the expression of their downstream pro‐apoptotic effector p27kip1, a cyclin‐dependent kinase inhibitor. Elevation of miR‐221 was found to contribute to the development of acquired lapatinib resistance by targeting p27kip1 expression. Furthermore, upregulation of miR‐221 was mediated by the lapatinib‐induced Src family tyrosine kinase and subsequent NF‐κB activation. The reversal of miR‐221 upregulation and p27kip1 downregulation by a Src inhibitor, dasatinib, can overcome lapatinib resistance. Our study not only identified miRNA‐221 as a pivotal factor conferring the acquired resistance of HER2‐positive breast cancer cells to lapatinib through negatively regulating p27kip1 expression, but also suggested Src inhibition as a potential strategy to overcome lapatinib resistance.
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Affiliation(s)
- Thanh Kieu Huynh
- Graduate Institute of Biomedical Sciences, Drug Development Center, China Medical University, Taichung, 404, Taiwan.,Center for Molecular Medicine, China Medical University Hospital, Taichung, 404, Taiwan
| | - Chih-Hao Huang
- Graduate Institute of Biomedical Sciences, Drug Development Center, China Medical University, Taichung, 404, Taiwan.,Division of Breast Surgery, China Medical University Hospital, Taichung, 40402, Taiwan
| | - Jhen-Yu Chen
- Graduate Institute of Biomedical Sciences, Drug Development Center, China Medical University, Taichung, 404, Taiwan
| | - Jin-Han Yao
- School of Medicine, China Medical University, Taichung, 404, Taiwan
| | - Yi-Shiang Yang
- Center for Molecular Medicine, China Medical University Hospital, Taichung, 404, Taiwan
| | - Ya-Ling Wei
- Center for Molecular Medicine, China Medical University Hospital, Taichung, 404, Taiwan
| | - Hsiao-Fan Chen
- Center for Molecular Medicine, China Medical University Hospital, Taichung, 404, Taiwan
| | - Chia-Hung Chen
- School of Medicine, China Medical University, Taichung, 404, Taiwan.,Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, 40402, Taiwan
| | - Chih-Yen Tu
- School of Medicine, China Medical University, Taichung, 404, Taiwan.,Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, 40402, Taiwan
| | - Yuan-Man Hsu
- Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan.,Department of Animal Science and Technology, Agriculture College, Tunghai University, Taichung, 40704, Taiwan
| | - Liang-Chih Liu
- Division of Breast Surgery, China Medical University Hospital, Taichung, 40402, Taiwan.,School of Medicine, China Medical University, Taichung, 404, Taiwan
| | - Wei-Chien Huang
- Graduate Institute of Biomedical Sciences, Drug Development Center, China Medical University, Taichung, 404, Taiwan.,Center for Molecular Medicine, China Medical University Hospital, Taichung, 404, Taiwan.,The Ph.D. program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, 404, Taiwan.,Department of Biotechnology, Asia University, Taichung, 413, Taiwan
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21
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Bernhardt SM, Dasari P, Glynn DJ, Townsend AR, Price TJ, Ingman WV. Comparison of hormone-induced mRNA and protein biomarker expression changes in breast cancer cells. Breast Cancer Res Treat 2021; 187:681-693. [PMID: 34057651 DOI: 10.1007/s10549-021-06254-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 05/04/2021] [Indexed: 11/29/2022]
Abstract
PURPOSE Protein biomarkers estrogen receptor (ER), progesterone receptor (PR), and marker of proliferation (Ki67) are routinely assessed by immunohistochemistry to guide treatment decisions for breast cancer. Now, quantification of mRNA encoding these proteins is being adopted in the clinic. However, mRNA and protein biomarkers may be differentially regulated by fluctuations in estrogen and progesterone that occur across the menstrual cycle in premenopausal breast cancer patients. This study aimed to compare how estrogen and progesterone affect mRNA and protein biomarker expression in hormone-responsive breast cancer cells. METHODS Hormone-responsive ZR-75-1 and T-47D human breast cancer cell lines were xenografted into the mammary fat pad of BALB/c nude mice supplemented with estrogen. Progesterone or vehicle was administered prior to dissection of tumors. Protein expression of ER, PR and Ki67 was quantified by immunohistochemistry, and mRNA encoding these proteins, ESR1, PGR and KI67, respectively, was quantified by real-time PCR. mRNA expression was also quantified in breast cancer cell lines treated with estrogen and progesterone in vitro. RESULTS In T-47D-xenografted tumors, estrogen and progesterone treatment reduced PGR and KI67 mRNA expression, and reduced PR and Ki67 protein positivity, compared to estrogen treatment alone. In ZR-75-1 xenografted tumors, no significant differences in protein or mRNA biomarker expression were observed. In vitro, estrogen and progesterone co-treatment significantly reduced ESR1 and PGR mRNA expression in both T-47D and ZR-75-1 cell lines. CONCLUSIONS Estrogen and progesterone similarly affect mRNA and protein biomarker expression in hormone-responsive breast cancer xenografts. Further research is needed to investigate concordance between protein and mRNA biomarkers in premenopausal breast cancer.
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Affiliation(s)
- Sarah M Bernhardt
- Discipline of Surgery, Adelaide Medical School, The Queen Elizabeth Hospital, University of Adelaide, DX465702, 28 Woodville Rd, Woodville, Adelaide, SA, 5011, Australia.,Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia
| | - Pallave Dasari
- Discipline of Surgery, Adelaide Medical School, The Queen Elizabeth Hospital, University of Adelaide, DX465702, 28 Woodville Rd, Woodville, Adelaide, SA, 5011, Australia.,Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia
| | - Danielle J Glynn
- Discipline of Surgery, Adelaide Medical School, The Queen Elizabeth Hospital, University of Adelaide, DX465702, 28 Woodville Rd, Woodville, Adelaide, SA, 5011, Australia.,Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia
| | - Amanda R Townsend
- Discipline of Surgery, Adelaide Medical School, The Queen Elizabeth Hospital, University of Adelaide, DX465702, 28 Woodville Rd, Woodville, Adelaide, SA, 5011, Australia.,Department of Medical Oncology, The Queen Elizabeth Hospital, Adelaide, SA, Australia
| | - Timothy J Price
- Discipline of Surgery, Adelaide Medical School, The Queen Elizabeth Hospital, University of Adelaide, DX465702, 28 Woodville Rd, Woodville, Adelaide, SA, 5011, Australia.,Department of Medical Oncology, The Queen Elizabeth Hospital, Adelaide, SA, Australia
| | - Wendy V Ingman
- Discipline of Surgery, Adelaide Medical School, The Queen Elizabeth Hospital, University of Adelaide, DX465702, 28 Woodville Rd, Woodville, Adelaide, SA, 5011, Australia. .,Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.
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22
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Goyal P, Doval DC, Agarwal C, Jain P, Chaudhari K, Domadia K, Redhu P, Koyyala VPB, Goel V, Batra U, Talwar V, Bothra S. Current Treatment Approaches for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in Adjuvant and Neoadjuvant Settings. Indian J Med Paediatr Oncol 2021. [DOI: 10.1055/s-0041-1729726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
AbstractBreast cancer (BC) is the second most common cancer and the second leading cause of mortality among women globally. Approximately 20 to 25% of BC patients have amplification of the human epidermal growth factor receptor 2 (HER2) genes, a marker of poor prognosis. However, the introduction of anti-HER2-therapies (trastuzumab, followed closely by lapatinib, pertuzumab, trastuzumab emtansine, and neratinib) has changed the natural history of HER2-positive BC and improved the outcome in HER2-positive BC patients. The preeminence of anti-HER2 combination therapy in achieving complete inhibition of the various HER receptor dimers has been demonstrated in clinical studies. However, despite these therapeutic advances, tumors expressing estrogen receptor have poorer responses to targeted therapy and are more likely to relapse. A better understanding of resistance to existing anti-HER2 agents, along with the role played by the microenvironment and of interconnected signaling pathways, can permit tailor-made therapeutic options for each patient. This review aimed to evaluate treatment approaches for BC patients with HER2-positive disease in the adjuvant and neoadjuvant settings, also exploring the possibilities of extended duration of anti-HER2 maintenance therapy.
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Affiliation(s)
- Pankaj Goyal
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Dinesh Chandra Doval
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Chaturbhuj Agarwal
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Parveen Jain
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Krushna Chaudhari
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Kshitij Domadia
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Pallavi Redhu
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | | | - Varun Goel
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Ullas Batra
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Vineet Talwar
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
| | - Sneha Bothra
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research, New Delhi, India
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23
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Ligorio F, Pellegrini I, Castagnoli L, Vingiani A, Lobefaro R, Zattarin E, Santamaria M, Pupa SM, Pruneri G, de Braud F, Vernieri C. Targeting lipid metabolism is an emerging strategy to enhance the efficacy of anti-HER2 therapies in HER2-positive breast cancer. Cancer Lett 2021; 511:77-87. [PMID: 33961924 DOI: 10.1016/j.canlet.2021.04.023] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 04/23/2021] [Accepted: 04/26/2021] [Indexed: 12/24/2022]
Abstract
De novo or acquired resistance of cancer cells to currently available Human Epidermal Growth Factor Receptor 2 (HER2) inhibitors represents a clinical challenge. Several resistance mechanisms have been identified in recent years, with lipid metabolism reprogramming, a well-established hallmark of cancer, representing the last frontier of preclinical and clinical research in this field. Fatty Acid Synthase (FASN), the key enzyme required for fatty acids (FAs) biosynthesis, is frequently overexpressed/activated in HER2-positive (HER2+) breast cancer (BC), and it crucially sustains HER2+ BC cell growth, proliferation and survival. After the synthesis of new, selective and well tolerated FASN inhibitors, clinical trials have been initiated to test if these compounds are able to re-sensitize cancer cells with acquired resistance to HER2 inhibition. More recently, the upregulation of FA uptake by cancer cells has emerged as a potentially new and targetable mechanism of resistance to anti-HER2 therapies in HER2+ BC, thus opening a new era in the field of targeting metabolic reprogramming in clinical setting. Here, we review the available preclinical and clinical evidence supporting the inhibition of FA biosynthesis and uptake in combination with anti-HER2 therapies in patients with HER2+ BC, and we discuss ongoing clinical trials that are investigating these combination approaches.
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Affiliation(s)
- Francesca Ligorio
- Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Ilaria Pellegrini
- Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Lorenzo Castagnoli
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy
| | - Andrea Vingiani
- Pathology Department, Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133, Milan, Italy; Department of Oncology and Haematology, University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy
| | - Riccardo Lobefaro
- Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Emma Zattarin
- Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Marzia Santamaria
- IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, Milan, Italy
| | - Serenella M Pupa
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy
| | - Giancarlo Pruneri
- Pathology Department, Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133, Milan, Italy; Department of Oncology and Haematology, University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy
| | - Filippo de Braud
- Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy; Department of Oncology and Haematology, University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy
| | - Claudio Vernieri
- Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy; IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, Milan, Italy.
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24
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Zoeller JJ, Press MF, Selfors LM, Dering J, Slamon DJ, Hurvitz SA, Brugge JS. Clinical evaluation of BCL-2/XL levels pre- and post- HER2-targeted therapy. PLoS One 2021; 16:e0251163. [PMID: 33951110 PMCID: PMC8099090 DOI: 10.1371/journal.pone.0251163] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 04/16/2021] [Indexed: 12/13/2022] Open
Abstract
Our previous pre-clinical work defined BCL-2 induction as a critical component of the adaptive response to lapatinib-mediated inhibition of HER2. To determine whether a similar BCL-2 upregulation occurs in lapatinib-treated patients, we evaluated gene expression within tumor biopsies, collected before and after lapatinib or trastuzumab treatment, from the TRIO-B-07 clinical trial (NCT#00769470). We detected BCL2 mRNA upregulation in both HER2+/ER- as well as HER2+/ER+ patient tumors treated with lapatinib or trastuzumab. To address whether mRNA expression correlated with protein expression, we evaluated pre- and post-treatment tumors for BCL-2 via immunohistochemistry. Despite BCL2 mRNA upregulation within HER2+/ER- tumors, BCL-2 protein levels were undetectable in most of the lapatinib- or trastuzumab-treated HER2+/ER- tumors. BCL-2 upregulation was evident within the majority of lapatinib-treated HER2+/ER+ tumors and was often coupled with increased ER expression and decreased proliferation. Comparable BCL-2 upregulation was not observed within the trastuzumab-treated HER2+/ER+ tumors. Together, these results provide clinical validation of the BCL-2 induction associated with the adaptive response to lapatinib and support evaluation of BCL-2 inhibitors within the context of lapatinib and other HER2-targeted receptor tyrosine kinase inhibitors.
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Affiliation(s)
- Jason J. Zoeller
- Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Michael F. Press
- Pathology, University of Southern California, Los Angeles, California, United States of America
| | - Laura M. Selfors
- Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Judy Dering
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine University of California, Jonsson Comprehensive Cancer Center, Los Angeles, California, United States of America
| | - Dennis J. Slamon
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine University of California, Jonsson Comprehensive Cancer Center, Los Angeles, California, United States of America
| | - Sara A. Hurvitz
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine University of California, Jonsson Comprehensive Cancer Center, Los Angeles, California, United States of America
| | - Joan S. Brugge
- Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail:
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25
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Kam AYF, Piryani SO, Lee CL, Rizzieri DA, Spector NL, Sarantopoulos S, Doan PL. Selective ERBB2 and BCL2 Inhibition Is Synergistic for Mitochondrial-Mediated Apoptosis in MDS and AML Cells. Mol Cancer Res 2021; 19:886-899. [PMID: 33514658 DOI: 10.1158/1541-7786.mcr-20-0973] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 12/23/2020] [Accepted: 01/21/2021] [Indexed: 11/16/2022]
Abstract
The ERBB2 proto-oncogene is associated with an aggressive phenotype in breast cancer. Its role in hematologic malignancies is incompletely defined, in part because ERBB2 is not readily detected on the surface of cancer cells. We demonstrate that truncated ERBB2, which lacks the extracellular domain, is overexpressed on primary CD34+ myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cells compared with healthy hematopoietic cells. This overexpression of ERBB2 is associated with aberrant, oncogenic signaling with autophosphorylation of multiple tyrosine sites. Like in breast cancers, ERBB2 can exist as truncated isoforms p95ERBB2 and p110ERBB2 in MDS and AML. Neutralization of ERBB2 signaling with ERBB2 tyrosine kinase inhibitors (i.e., lapatinib, afatinib, and neratinib) increases apoptotic cell death and reduces human engraftment of MDS cells in mice at 21 weeks posttransplantation. Inhibition of ERBB2 modulates the expression of multiple pro- and anti-apoptotic mitochondrial proteins, including B-cell lymphoma 2 (BCL2). Dual blockade with ERBB2 and BCL2 inhibitors triggers additional reductions of BCL2 phosphorylation and myeloid cell leukemia-1 (MCL1) expression compared with single drug treatment. Dual therapy was synergistic at all tested doses, with a dose reduction index of up to 29 for lapatinib + venetoclax compared with venetoclax alone. Notably, these agents operated together and shifted cancer cells to a pro-apoptotic phenotype, resulting in increased mitochondrial cytochrome c release and activated caspase-3-mediated cell death. IMPLICATIONS: These findings warrant study of ERBB2 and BCL2 combination therapy in patients with MDS and AML. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/5/886/F1.large.jpg.
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Affiliation(s)
- Angel Y F Kam
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, North Carolina
| | - Sadhna O Piryani
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, North Carolina
| | - Chang-Lung Lee
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.,Department of Pathology, Duke University Medical Center, Durham, North Carolina.,Duke Cancer Institute, Duke University, Durham, North Carolina
| | - David A Rizzieri
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, North Carolina.,Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Neil L Spector
- Duke Cancer Institute, Duke University, Durham, North Carolina.,Division of Medical Oncology, Department of Medicine, Duke University, Durham, North Carolina
| | - Stefanie Sarantopoulos
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, North Carolina.,Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Phuong L Doan
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, North Carolina. .,Duke Cancer Institute, Duke University, Durham, North Carolina
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26
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Brahm CG, Abdul UK, Houweling M, van Linde ME, Lagerweij T, Verheul HMW, Westerman BA, Walenkamp AME, Fehrmann RSN. Data-driven prioritization and preclinical evaluation of therapeutic targets in glioblastoma. Neurooncol Adv 2021; 2:vdaa151. [PMID: 33392504 PMCID: PMC7764503 DOI: 10.1093/noajnl/vdaa151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background Patients with glioblastoma (GBM) have a dismal prognosis, and there is an unmet need for new therapeutic options. This study aims to identify new therapeutic targets in GBM. Methods mRNA expression data of patient-derived GBM (n = 1279) and normal brain tissue (n = 46) samples were collected from Gene Expression Omnibus and The Cancer Genome Atlas. Functional genomic mRNA profiling was applied to capture the downstream effects of genomic alterations on gene expression levels. Next, a class comparison between GBM and normal brain tissue was performed. Significantly upregulated genes in GBM were further prioritized based on (1) known interactions with antineoplastic drugs, (2) current drug development status in humans, and (3) association with biologic pathways known to be involved in GBM. Antineoplastic agents against prioritized targets were validated in vitro and in vivo. Results We identified 712 significantly upregulated genes in GBM compared to normal brain tissue, of which 27 have a known interaction with antineoplastic agents. Seventeen of the 27 genes, including EGFR and VEGFA, have been clinically evaluated in GBM with limited efficacy. For the remaining 10 genes, RRM2, MAPK9 (JNK2, SAPK1a), and XIAP play a role in GBM development. We demonstrated for the MAPK9 inhibitor RGB-286638 a viability loss in multiple GBM cell culture models. Although no overall survival benefit was observed in vivo, there were indications that RGB-286638 may delay tumor growth. Conclusions The MAPK9 inhibitor RGB-286638 showed promising in vitro results. Furthermore, in vivo target engagement studies and combination therapies with this compound warrant further exploration.
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Affiliation(s)
- Cyrillo G Brahm
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Medical Oncology, Cancer Center Amsterdam, Brain Tumor Center Amsterdam, Amsterdam University Medical Centers, Location VUmc, Amsterdam, The Netherlands
| | - U Kulsoom Abdul
- Department of Neurosurgery, Cancer Center Amsterdam, Brain Tumor Center Amsterdam, Amsterdam University Medical Centers, Location VUmc, Amsterdam, The Netherlands
| | - Megan Houweling
- Department of Neurosurgery, Cancer Center Amsterdam, Brain Tumor Center Amsterdam, Amsterdam University Medical Centers, Location VUmc, Amsterdam, The Netherlands
| | - Myra E van Linde
- Department of Medical Oncology, Cancer Center Amsterdam, Brain Tumor Center Amsterdam, Amsterdam University Medical Centers, Location VUmc, Amsterdam, The Netherlands
| | - Tonny Lagerweij
- Department of Neurosurgery, Cancer Center Amsterdam, Brain Tumor Center Amsterdam, Amsterdam University Medical Centers, Location VUmc, Amsterdam, The Netherlands
| | - Henk M W Verheul
- Department of Medical Oncology, Cancer Center Amsterdam, Brain Tumor Center Amsterdam, Amsterdam University Medical Centers, Location VUmc, Amsterdam, The Netherlands.,Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Bart A Westerman
- Department of Neurosurgery, Cancer Center Amsterdam, Brain Tumor Center Amsterdam, Amsterdam University Medical Centers, Location VUmc, Amsterdam, The Netherlands
| | - Annemiek M E Walenkamp
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rudolf S N Fehrmann
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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27
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Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor–Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. J Clin Oncol 2021; 39:79-89. [DOI: 10.1200/jco.20.01894] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Human epidermal growth factor receptor 2 (HER2) targeting plus endocrine therapy (ET) improved clinical benefit in HER2-positive, hormone receptor (HR)–positive metastatic breast cancer (MBC) versus ET alone. Dual HER2 blockade enhances clinical benefit versus single HER2 blockade. The ALTERNATIVE study evaluated the efficacy and safety of dual HER2 blockade plus aromatase inhibitor (AI) in postmenopausal women with HER2-positive/HR-positive MBC who received prior ET and prior neo(adjuvant)/first-line trastuzumab (TRAS) plus chemotherapy. This updated article reflects minor numerical corrections in some secondary efficacy analyses that resulted from programming errors and that do not change the major conclusions of the study. METHODS Patients were randomly assigned (1:1:1) to receive lapatinib (LAP) plus TRAS plus AI, TRAS plus AI, or LAP plus AI. Patients for whom chemotherapy was intended were excluded. The primary end point was progression-free survival (PFS; investigator assessed) with LAP plus TRAS plus AI versus TRAS plus AI. Secondary end points were PFS (comparison of other arms), overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and safety. RESULTS Three hundred fifty-five patients were included in this analysis: LAP plus TRAS plus AI (n = 120), TRAS plus AI (n = 117), and LAP plus AI (n = 118). Baseline characteristics were balanced. The study met its primary end point; superior PFS was observed with LAP plus TRAS plus AI versus TRAS plus AI (median PFS, 11 v 5.6 months; hazard ratio, 0.62 [95% CI, 0.45 to 0.88]; P = .0063). A consistent PFS benefit was observed in predefined subgroups. ORR, CBR, and OS also favored LAP plus TRAS plus AI. The median PFS with LAP plus AI versus TRAS plus AI was 8.3 versus 5.6 months (hazard ratio, 0.85 [95% CI, 0.62 to 1.17]; P = .3159). Common adverse events (AEs; ≥ 15%) with LAP plus TRAS plus AI, TRAS plus AI, and LAP plus AI were diarrhea (69%, 9%, and 51%, respectively), rash (36%, 2%, and 28%, respectively), nausea (22%, 9%, and 22%, respectively), and paronychia (30%, 0%, and 15%, respectively), mostly grade 1 or 2. Serious AEs were reported similarly across the 3 groups, and AEs leading to discontinuation were lower with LAP plus TRAS plus AI. CONCLUSION Dual HER2 blockade with LAP plus TRAS plus AI showed superior PFS benefit versus TRAS plus AI in patients with HER2-positive/HR-positive MBC. This combination offers an effective and safe chemotherapy-sparing alternative treatment regimen for this patient population.
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Affiliation(s)
| | - Roberto Hegg
- Centro de Referência da Saúde da Mulher, São Paulo, Brazil
| | - Seock-Ah Im
- Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | | | | | | | | | | | | | | | | | | | | | | | - William J. Gradishar
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL
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Cheun JH, Won J, Jung JG, Kim HK, Han W, Lee HB. Impact of Trastuzumab on Ipsilateral Breast Tumor Recurrence for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer after Breast-Conserving Surgery. J Breast Cancer 2021; 24:301-314. [PMID: 34190441 PMCID: PMC8250103 DOI: 10.4048/jbc.2021.24.e33] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 04/06/2021] [Accepted: 04/19/2021] [Indexed: 11/30/2022] Open
Abstract
Purpose Trastuzumab is effective in early and advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, few studies have reported the effect of trastuzumab on ipsilateral breast tumor recurrence (IBTR), whose incidence is higher in the HER2-positive subtype than in other subtypes. Methods We retrospectively investigated 959 patients who underwent breast-conserving surgery (BCS), chemotherapy, and radiotherapy for HER2-positive breast cancer between 2000 and 2017. IBTR was compared between the patients who received neoadjuvant or adjuvant trastuzumab (Tmab group) for a total duration of 1 year and those who received no trastuzumab (N-Tmab group). Results Propensity score matching designated 426 and 142 patients in the Tmab and N-Tmab groups, respectively. The median follow-up period for all patients after matching was 73.79 months. The IBTR-free survival rate was significantly higher in the Tmab group than in the N-Tmab group (10-year IBTR-free survival rate, 92.9% vs. 87.3%; p = 0.002). The multivariate analysis showed a significant association between the N-Tmab and Tmab group (hazard ratio, 3.03; 95% confidence interval, 1.07–8.59) and IBTR in addition to close or positive resection margin and hormone receptor (HR) positivity. The subgroup analysis showed that adjuvant treatment with trastuzumab significantly reduced IBTR among the patients with HR-negative or lymph node-negative breast cancer. Conclusion Significantly reduced IBTR after BCS was observed in the patients who received 1 year of adjuvant/neoadjuvant trastuzumab treatment for HER2-positive breast cancer.
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Affiliation(s)
- Jong Ho Cheun
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Jiyoung Won
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea
| | - Ji Gwang Jung
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hong Kyu Kim
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Wonshik Han
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.,Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.,Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Han Byoel Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.,Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.,Cancer Research Institute, Seoul National University, Seoul, Korea.
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Abstract
Forkhead box O (FOXO) transcription factors regulate diverse biological processes, affecting development, metabolism, stem cell maintenance and longevity. They have also been increasingly recognised as tumour suppressors through their ability to regulate genes essential for cell proliferation, cell death, senescence, angiogenesis, cell migration and metastasis. Mechanistically, FOXO proteins serve as key connection points to allow diverse proliferative, nutrient and stress signals to converge and integrate with distinct gene networks to control cell fate, metabolism and cancer development. In consequence, deregulation of FOXO expression and function can promote genetic disorders, metabolic diseases, deregulated ageing and cancer. Metastasis is the process by which cancer cells spread from the primary tumour often via the bloodstream or the lymphatic system and is the major cause of cancer death. The regulation and deregulation of FOXO transcription factors occur predominantly at the post-transcriptional and post-translational levels mediated by regulatory non-coding RNAs, their interactions with other protein partners and co-factors and a combination of post-translational modifications (PTMs), including phosphorylation, acetylation, methylation and ubiquitination. This review discusses the role and regulation of FOXO proteins in tumour initiation and progression, with a particular emphasis on cancer metastasis. An understanding of how signalling networks integrate with the FOXO transcription factors to modulate their developmental, metabolic and tumour-suppressive functions in normal tissues and in cancer will offer a new perspective on tumorigenesis and metastasis, and open up therapeutic opportunities for malignant diseases.
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Affiliation(s)
- Yannasittha Jiramongkol
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Eric W-F Lam
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK.
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30
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Geneste A, Duong MN, Molina L, Conilh L, Beaumel S, Cleret A, Chettab K, Lachat M, Jordheim LP, Matera EL, Dumontet C. Adipocyte-conditioned medium induces resistance of breast cancer cells to lapatinib. BMC Pharmacol Toxicol 2020; 21:61. [PMID: 32795383 PMCID: PMC7427918 DOI: 10.1186/s40360-020-00436-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 07/27/2020] [Indexed: 12/22/2022] Open
Abstract
Background The existence of a cross-talk between peritumoral adipocytes and cancer cells has been increasingly investigated. Several studies have shown that these adipocytes protect tumor cells from the effect of anticancer agents. Methods To investigate a potential protective effect of adipocyte-conditioned medium on HER2 positive breast cancer cells exposed to tyrosine kinase inhibitors (TKI) such as lapatinib, we analyzed the sensitivity of HER2 positive breast cancer models in vitro and in vivo on SCID mice in the presence or absence of adipocytes or adipocyte-conditioned medium. Results Conditioned medium from differentiated adipocytes reduced the in vitro sensitivity of the HER2+ cell lines BT474 and SKBR3 to TKI. Particularly, conditioned medium abrogated P27 induction in tumor cells by lapatinib but this was observed only when conditioned medium was present during exposure to lapatinib. In addition, resistance was induced with adipocytes derived from murine NIH3T3 or human hMAD cells but not with fibroblasts or preadipocytes. In vivo studies demonstrated that the contact of the tumors with adipose tissue reduced sensitivity to lapatinib. Soluble factors involved in this resistance were found to be thermolabile. Pharmacological modulation of lipolysis in adipocytes during preparation of conditioned media showed that various lipolysis inhibitors abolished the protective effect of conditioned media on tumor cells, suggesting a role for adipocyte lipolysis in the induction of resistance of tumor cells to TKI. Conclusions Overall, our results suggest that contact of tumor cells with proximal adipose tissue induces resistance to anti HER2 small molecule inhibitors through the production of soluble thermolabile factors, and that this effect can be abrogated using lipolysis inhibitors.
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Affiliation(s)
- A Geneste
- Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France
| | - M N Duong
- Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Epalinges, Switzerland
| | - L Molina
- Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France
| | - L Conilh
- Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France.
| | - S Beaumel
- Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France
| | - A Cleret
- Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France
| | - K Chettab
- Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France
| | - M Lachat
- Hospices Civils de Lyon, Banque de tissus et cellules, 5 place d'Arsonval, 69003, Lyon, France
| | - L P Jordheim
- Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France
| | - E L Matera
- Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France
| | - C Dumontet
- Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052, CNRS 5286, 8 Avenue Rockefeller, 69008, Lyon, France.,Hospices Civils de Lyon, Services d'Hématologie, 165 Chemin du Grand Revoyet, 69310, Pierre-Bénite, France
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Patel A, Unni N, Peng Y. The Changing Paradigm for the Treatment of HER2-Positive Breast Cancer. Cancers (Basel) 2020; 12:cancers12082081. [PMID: 32731409 PMCID: PMC7464074 DOI: 10.3390/cancers12082081] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/16/2020] [Accepted: 07/22/2020] [Indexed: 01/01/2023] Open
Abstract
For decades, HER2-positive breast cancer was associated with poor outcomes and higher mortality rates than other breast cancer subtypes. However, the advent of Trastuzumab (Herceptin) has significantly changed the treatment paradigm of patients afflicted with HER2-positive breast cancer. The discovery of newer HER2-targeted therapies, such as Pertuzumab (Perjeta), has further added to the armamentarium of treating HER2-positive breast cancers. This review highlights recent advancements in the treatment of HER2-positive diseases, including the newer HER2-targeted therapies and immunotherapies in clinical trials, which have paved (and will further update) the way for clinical practice, and become part of the standard of care in the neoadjuvant, adjuvant or metastatic setting.
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Affiliation(s)
- Aena Patel
- Department of Internal Medicine, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
| | - Nisha Unni
- Department of Internal Medicine, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
- Correspondence: (N.U.); (Y.P.)
| | - Yan Peng
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Correspondence: (N.U.); (Y.P.)
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Zhang M, Li L, Zhang S, Zhu W, Yang S, Di G, Ma X, Yang H. Efficacy of Neoadjuvant Chemotherapy with Epirubicin and Cyclophosphamide and Weekly Paclitaxel and Trastuzumab in Human Epidermal Growth Factor Receptor 2-Positive Breast Carcinoma: A Real-World Study. BIOMED RESEARCH INTERNATIONAL 2020; 2020:3208391. [PMID: 32461977 PMCID: PMC7222597 DOI: 10.1155/2020/3208391] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 12/29/2019] [Accepted: 01/16/2020] [Indexed: 11/17/2022]
Abstract
BACKGROUND Trastuzumab has been introduced a decade ago and demonstrated improvement in the prognosis in patients with human epidermal growth factor receptor 2- (HER2-) positive (+) breast carcinoma (BC). This study is aimed at evaluating the efficacy of epirubicin/cyclophosphamide with weekly paclitaxel-trastuzumab as neoadjuvant chemotherapies in HER2+ BC patients. METHODS A total of 234 HER2+ BC patients were given neoadjuvant chemotherapy (NAC) between 2010 and 2016. The primary endpoints were pathologic complete response (pCR) and disease-free survival (DFS). Univariate and multivariate analyses of clinical and pathological factors associated with pCR and DFS were conducted. RESULTS The pCR (30.4% vs. 14.8%; P = 0.004) and DFS (P = 0.036) showed significant differences between patients administered with neoadjuvant trastuzumab therapy and those who did not. Multivariate logistic regression analysis showed that neoadjuvant trastuzumab treatment was regarded as an independent predictor of pCR. Patients with pCR had prolonged DFS (P = 0.025). In patients who did not achieve pCR (non-pCR), those who received trastuzumab had more prolonged DFS (P = 0.046). The luminal B/HER2+ subtypes had prolonged DFS when compared with nonluminal B/HER2+ subtypes (P = 0.010). The luminal B/HER2+ subgroup also showed improved DFS in non-pCR patients (P = 0.010). In the subgroup of non-pCR, the luminal B/HER2+ subgroup administered with trastuzumab showed no superior DFS (P = 0.168). However, a positive result was observed in patients without trastuzumab (P = 0.039). Multivariate analysis showed cT stage (P = 0.006) and tumor grade (P = 0.041), considering them as significant prognostic factors of DFS. CONCLUSIONS HER2+ BC patients showed improvement in pCR and DFS after neoadjuvant trastuzumab treatment. Patients without pCR had prolonged DFS after trastuzumab maintenance. Although the prognosis of luminal B/HER2+ BC showed favorable outcomes in the non-pCR subgroup, those receiving trastuzumab showed no survival advantage.
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Affiliation(s)
- Mengmeng Zhang
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou 550004, China
| | - Ling Li
- Department of Neurology, 925 Hospital of PLA Joint Logistics Support Force, Guizhou 550009, China
| | - Shiyong Zhang
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou 550004, China
| | - Wenlong Zhu
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou 550004, China
| | - Senguo Yang
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou 550004, China
| | - Guangsheng Di
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou 550004, China
| | - Xiaoxia Ma
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou 550004, China
| | - Haisong Yang
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou 550004, China
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Crosstalk between Epidermal Growth Factor Receptors (EGFR) and integrins in resistance to EGFR tyrosine kinase inhibitors (TKIs) in solid tumors. Eur J Cell Biol 2020; 99:151083. [PMID: 32381360 DOI: 10.1016/j.ejcb.2020.151083] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/17/2020] [Accepted: 04/18/2020] [Indexed: 12/21/2022] Open
Abstract
Cell adhesion to the extracellular matrix (ECM) is important in a variety of physiological and pathologic processes, including development, tumor invasion, and metastasis. Integrin-mediated attachment to ECM proteins has emerged to cue events primitively important for the transformed phenotype of human cancer cells. Cross-talk between integrins and growth factor receptors takes an increasingly prominent role in defining adhesion, motility, and cell growth. This functional interaction has expanded beyond to link integrins with resistance to Tyrosine kinase inhibitors (TKIs) of Epidermal Growth Factor Receptors (EGFRs). In this regard, integrin-mediated adhesion has two separate functions one as a clear collaborator with growth factor receptor signaling and the second as a basic mechanism contributing in Epithelial to Mesenchymal Transition (EMT) which affects response to chemotherapy. This review provides an overview of these mechanisms and describes treatment options for selectively targeting and disrupting integrin interaction to EGFR for cancer therapy.
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Kreutzfeldt J, Rozeboom B, Dey N, De P. The trastuzumab era: current and upcoming targeted HER2+ breast cancer therapies. Am J Cancer Res 2020; 10:1045-1067. [PMID: 32368385 PMCID: PMC7191090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 02/28/2020] [Indexed: 06/11/2023] Open
Abstract
Human Epidermal Growth Factor Receptor 2-positive breast cancer (HER2+ BC) is defined by increased amplification of the ERBB2/neu oncogene and/or overexpression of its associated HER2 transmembrane receptor protein. HER2+ BC represents approximately 15-20% of breast cancer, and it is independently associated with a higher grade, more aggressive phenotype, and worse prognosis. With the advent of trastuzumab, the prognostic landscape for HER2+ BC patients has considerably improved. However, both de novo and acquired resistance to trastuzumab remain a significant obstacle for many patients, requiring novel therapies for further clinical benefit. Over the last two decades, there has been extraordinary progress in the development of HER2+ BC treatment regimens, with extensions into HER2-amplified gastroesophageal junction cancer via the NCI-MATCH precision medicine trial program (NCT02465060). Trastuzumab, pertuzumab, T-DM1, and lapatinib are commonly recommended as a single agent (along with chemotherapy) or in combinations of anti-HER2 agents in neoadjuvant, adjuvant and metastatic settings according to National Comprehensive Cancer Network (NCCN) guidelines. Currently, the combination of trastuzumab, pertuzumab, and taxane chemotherapy are first-line for HER2+/HR- metastatic breast cancer with potential breakthrough therapies such as trastuzumab-deruxtecan (DS-8201a), margetuximab and tucatinib (ONT-380) on the horizon. Furthermore, recent clinical trials have demonstrated the potential utility of hormone receptor status, PAM-50 luminal intrinsic subtype, PD-L1, and TIL as predictive biomarkers for response to HER2+ therapies. We briefly introduce the origin of HER2, the invention of trastuzumab, and the classification of HER2+ BC. Each HER2-targeted therapy is then presented by indication, mechanism of action, and relevant clinical trials with subsequent elaboration and contextualization within clinical settings with an epilogue of potential future biomarkers for clinical use in HER2+ BC. We summarize the most significant and updated research in clinical practice relevant to HER2+ BC management and highlight the clinical status of upcoming anti-HER2 agents as well as immunotherapy drugs in combination with anti-HER2 agents.
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Affiliation(s)
- Jordyn Kreutzfeldt
- Translation Oncology Laboratory, Avera Cancer InstituteSioux Falls, SD 57105, USA
- Department of Internal Medicine, University of South Dakota Sanford School of MedicineSioux Falls, SD 57105, USA
| | - Brett Rozeboom
- Translation Oncology Laboratory, Avera Cancer InstituteSioux Falls, SD 57105, USA
- Department of Internal Medicine, University of South Dakota Sanford School of MedicineSioux Falls, SD 57105, USA
| | - Nandini Dey
- Translation Oncology Laboratory, Avera Cancer InstituteSioux Falls, SD 57105, USA
- Department of Internal Medicine, University of South Dakota Sanford School of MedicineSioux Falls, SD 57105, USA
| | - Pradip De
- Translation Oncology Laboratory, Avera Cancer InstituteSioux Falls, SD 57105, USA
- Department of Internal Medicine, University of South Dakota Sanford School of MedicineSioux Falls, SD 57105, USA
- VieCureGreenwood Village, CO, USA
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Goutsouliak K, Veeraraghavan J, Sethunath V, De Angelis C, Osborne CK, Rimawi MF, Schiff R. Towards personalized treatment for early stage HER2-positive breast cancer. Nat Rev Clin Oncol 2020; 17:233-250. [PMID: 31836877 PMCID: PMC8023395 DOI: 10.1038/s41571-019-0299-9] [Citation(s) in RCA: 190] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2019] [Indexed: 12/13/2022]
Abstract
Advances in HER2-targeted therapies have improved the survival of patients with HER2-positive breast cancer. The standard-of-care treatment for localized disease has been chemotherapy and 1 year of adjuvant HER2-targeted therapy, typically with the anti-HER2 antibody trastuzumab. Despite the effectiveness of this treatment, disease relapse occurs in a subset of patients; thus, focus has been placed on escalating treatment by either combining different HER2-targeted agents or extending the duration of HER2-targeted therapy. Indeed, dual HER2-targeted therapies and extended-duration anti-HER2 therapy, as well as adjuvant therapy with the anti-HER2 antibody-drug conjugate T-DM1, have all been approved for clinical use. Emerging evidence suggests, however, that some patients do not derive sufficient benefit from these additional therapies to offset the associated toxicities and/or costs. Similarly, the universal use of chemotherapy might not benefit all patients, and treatment de-escalation through omission of chemotherapy has shown promise in clinical trials and is currently being explored further. The future of precision medicine should therefore involve tailoring of therapy based on the genetics and biology of each tumour and the clinical characteristics of each patient. Predictive biomarkers that enable the identification of patients who will benefit from either escalated or de-escalated treatment will be crucial to this approach. In this Review, we summarize the available HER2-targeted agents and associated mechanisms of resistance, and describe the current therapeutic landscape of early stage HER2-positive breast cancer, focusing on strategies for treatment escalation or de-escalation.
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Affiliation(s)
- Kristina Goutsouliak
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Jamunarani Veeraraghavan
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Vidyalakshmi Sethunath
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Carmine De Angelis
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - C Kent Osborne
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Mothaffar F Rimawi
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
| | - Rachel Schiff
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
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Li X, Zhang K, Hu Y, Luo N. ERRα activates SHMT2 transcription to enhance the resistance of breast cancer to lapatinib via modulating the mitochondrial metabolic adaption. Biosci Rep 2020; 40:BSR20192465. [PMID: 31894856 PMCID: PMC6970080 DOI: 10.1042/bsr20192465] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 12/24/2019] [Accepted: 12/27/2019] [Indexed: 12/14/2022] Open
Abstract
Lapatinib, a tyrosine kinase inhibitor, can initially benefit the patients with breast tumors but fails in later treatment due to the inevitable development of drug resistance. Estrogen-related receptor α (ERRα) modulates the metabolic adaptations in lapatinib-resistant cancer cells; however, the underlying mechanism remains unclear. ERRα was predicted to bind to the serine hydroxymethyltransferase 2 (SHMT2) transcription initiation site in the ER- and HER2-positive cell line BT-474; thus, we hypothesize that ERRα might modulate the resistance of breast cancer to lapatinib via regulating SHMT2. In the present study, we revealed that 2.5 and 5 µM lapatinib treatment could significantly decrease the expression and protein levels of ERRα and SHMT2; ERRα and SHMT2 expression and protein levels were significantly up-regulated in breast cancer cells, in particularly in breast cancer cells with resistance to lapatinib. ERRα knockdown restored the inhibitory effects of lapatinib on the BT-474R cell viability and migration; in the meantime, ERRα knockdown rescued the production of reactive oxygen species (ROS) whereas decreased the ratio of glutathione (GSH)/oxidized glutathione (GSSG) upon lapatinib treatment. Via targeting SHMT2 promoter region, ERRα activated the transcription of SHMT2. The effects of ERRα knockdown on BT-474R cells under lapatinib treatment could be significantly reversed by SHMT2 overexpression. In conclusion, ERRα knockdown suppresses the detoxification and the mitochondrial metabolic adaption in breast cancer resistant to lapatinib; ERRα activates SHMT2 transcription via targeting its promoter region, therefore enhancing breast cancer resistance to lapatinib.
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Affiliation(s)
- Xin Li
- Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Kejing Zhang
- Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yu Hu
- Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Na Luo
- Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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Aimjongjun S, Mahmud Z, Jiramongkol Y, Alasiri G, Yao S, Yagüe E, Janvilisri T, Lam EWF. Lapatinib sensitivity in nasopharyngeal carcinoma is modulated by SIRT2-mediated FOXO3 deacetylation. BMC Cancer 2019; 19:1106. [PMID: 31727006 PMCID: PMC6854897 DOI: 10.1186/s12885-019-6308-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 10/29/2019] [Indexed: 12/13/2022] Open
Abstract
Background Chemoresistance is an obstacle to the successful treatment of nasopharyngeal carcinoma (NPC). Lapatinib is a targeted tyrosine kinase inhibitor therapeutic drug also used to treat NPC, but high doses are often required to achieve a result. To investigate the mechanism for the development of Lapatinib resistance, we characterised a number of NPC cell lines to determine the role of FOXO3 and sirtuins in regulating NPC resistance. Methods Sulforhodamine B (SRB) assays, Clonogenic assays, Protein extraction, quantification and western blotting, RT qPCR, Co-immunoprecipitation assay. Results To explore novel treatment strategies, we first characterized the Lapatinib-sensitivity of a panel of NPC cell lines by SRB and clonogenic cytotoxic assays and found that the metastatic NPC (C666–1 and 5-8F) cells are highly resistant whereas the poorly metastatic lines (6-10B, TW01 and HK-1) are sensitive to Lapatinib. Western blot analysis of the Lapatinib-sensitive 6-10B and resistant 5-8F NPC cells showed that the expression of phosphorylated/inactive FOXO3 (P-FOXO3;T32), its target FOXM1 and its regulator SIRT2 correlate negatively with Lapatinib response and sensitivity, suggesting that SIRT2 mediates FOXO3 deacetylation to promote Lapatinib resistance. In agreement, clonogenic cytotoxic assays using wild-type and foxo1/3/4−/− mouse embryonic fibroblasts (MEFs) showed that FOXO1/3/4-deletion significantly attenuates Lapatinib-induced cytotoxicity, confirming that FOXO proteins are essential for mediating Lapatinib response. SRB cell viability assays using chemical SIRT inhibitors (i.e. sirtinol, Ex527, AGK2 and AK1) revealed that all SIRT inhibitors can reduce NPC cell viability, but only the SIRT2-specific inhibitors AK1 and AGK2 further enhance the Lapatinib cytotoxicity. Consistently, clonogenic assays demonstrated that the SIRT2 inhibitors AK1 and AGK2 as well as SIRT2-knockdown increase Lapatinib cytotoxicity further in both the sensitive and resistant NPC cells. Co-immunoprecipitation studies showed that besides Lapatinib treatment, SIRT2-pharmaceutical inhibition and silencing also led to an increase in FOXO3 acetylation. Importantly, SIRT2 inhibition and depletion further enhanced Lapatinib-mediated FOXO3-acetylation in NPC cells. Conclusion Collectively, our results suggest the involvement of SIRT2-mediated FOXO3 deacetylation in Lapatinib response and sensitivity, and that SIRT2 can specifically antagonise the cytotoxicity of Lapatinib through mediating FOXO3 deacetylation in both sensitive and resistant NPC cells. The present findings also propose that SIRT2 can be an important biomarker for metastatic and Lapatinib resistant NPC and that targeting the SIRT2-FOXO3 axis may provide novel strategies for treating NPC and for overcoming chemoresistance.
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Affiliation(s)
- Sathid Aimjongjun
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK.,Graduate Program in Molecular Medicine, Multidisciplinary Unit, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Zimam Mahmud
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Yannasittha Jiramongkol
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Glowi Alasiri
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Shang Yao
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Ernesto Yagüe
- Graduate Program in Molecular Medicine, Multidisciplinary Unit, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Tavan Janvilisri
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Eric W-F Lam
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK.
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EP300 and SIRT1/6 Co-Regulate Lapatinib Sensitivity Via Modulating FOXO3-Acetylation and Activity in Breast Cancer. Cancers (Basel) 2019; 11:cancers11081067. [PMID: 31357743 PMCID: PMC6721388 DOI: 10.3390/cancers11081067] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 07/22/2019] [Accepted: 07/25/2019] [Indexed: 12/31/2022] Open
Abstract
Forkhead Box O3 (FOXO3) is a tumor suppressor whose activity is fine-tuned by post-translational modifications (PTMs). In this study, using the BT474 breast cancer cells and a recently established lapatinib resistant (BT474-LapR) cell line, we observed that higher FOXO3 and acetylated (Ac)-FOXO3 levels correlate with lapatinib sensitivity. Subsequent ectopic expression of EP300 led to an increase in acetylated-FOXO3 in sensitive but not in resistant cells. Drug sensitivity assays revealed that sensitive BT474 cells show increased lapatinib cytotoxicity upon over-expression of wild-type but not acetylation-deficient EP300. Moreover, FOXO3 recruitment to target gene promoters is associated with target gene expression and drug response in sensitive cells and the inability of FOXO3 to bind its target genes correlates with lapatinib-resistance in BT474-LapR cells. In addition, using SIRT1/6 specific siRNAs and chemical inhibitor, we also found that sirtuin 1 and -6 (SIRT1 and -6) play a part in fine-tuning FOXO3 acetylation and lapatinib sensitivity. Consistent with this, immunohistochemistry results from different breast cancer subtypes showed that high SIRT6/1 levels are associated with constitutive high FOXO3 expression which is related to FOXO3 deregulation/inactivation and poor prognosis in breast cancer patient samples. Collectively, our results suggest the involvement of FOXO3 acetylation in regulating lapatinib sensitivity of HER2-positive breast cancers.
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Resistance mechanisms to anti-HER2 therapies in HER2-positive breast cancer: Current knowledge, new research directions and therapeutic perspectives. Crit Rev Oncol Hematol 2019; 139:53-66. [DOI: 10.1016/j.critrevonc.2019.05.001] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 12/19/2018] [Accepted: 05/01/2019] [Indexed: 01/10/2023] Open
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Zoeller JJ, Vagodny A, Taneja K, Tan BY, O'Brien N, Slamon DJ, Sampath D, Leverson JD, Bronson RT, Dillon DA, Brugge JS. Neutralization of BCL-2/X L Enhances the Cytotoxicity of T-DM1 In Vivo. Mol Cancer Ther 2019; 18:1115-1126. [PMID: 30962322 PMCID: PMC6758547 DOI: 10.1158/1535-7163.mct-18-0743] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 01/08/2019] [Accepted: 04/02/2019] [Indexed: 12/11/2022]
Abstract
One of the most recent advances in the treatment of HER2+ breast cancer is the development of the antibody-drug conjugate, T-DM1. T-DM1 has proven clinical benefits for patients with advanced and/or metastatic breast cancer who have progressed on prior HER2-targeted therapies. However, T-DM1 resistance ultimately occurs and represents a major obstacle in the effective treatment of this disease. Because anti-apoptotic BCL-2 family proteins can affect the threshold for induction of apoptosis and thus limit the effectiveness of the chemotherapeutic payload, we examined whether inhibition of BCL-2/XL would enhance the efficacy of T-DM1 in five HER2-expressing patient-derived breast cancer xenograft models. Inhibition of BCL-2/XL via navitoclax/ABT-263 significantly enhanced the cytotoxicity of T-DM1 in two of three models derived from advanced and treatment-exposed metastatic breast tumors. No additive effects of combined treatment were observed in the third metastatic tumor model, which was highly sensitive to T-DM1, as well as a primary treatment-exposed tumor, which was refractory to T-DM1. A fifth model, derived from a treatment naïve primary breast tumor, was sensitive to T-DM1 but markedly benefited from combination treatment. Notably, both PDXs that were highly responsive to the combination therapy expressed low HER2 protein levels and lacked ERBB2 amplification, suggesting that BCL-2/XL inhibition can enhance sensitivity of tumors with low HER2 expression. Toxicities associated with combined treatments were significantly ameliorated with intermittent ABT-263 dosing. Taken together, these studies provide evidence that T-DM1 cytotoxicity could be significantly enhanced via BCL-2/XL blockade and support clinical investigation of this combination beyond ERBB2-amplified and/or HER2-overexpressed tumors.
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Affiliation(s)
- Jason J Zoeller
- Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts
| | - Aleksandr Vagodny
- Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts
| | - Krishan Taneja
- Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts
| | - Benjamin Y Tan
- Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts
| | - Neil O'Brien
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Dennis J Slamon
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Deepak Sampath
- Translational Oncology, Genentech, San Francisco, California
| | | | | | - Deborah A Dillon
- Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts
| | - Joan S Brugge
- Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.
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Omarini C, Bettelli S, Caprera C, Manfredini S, Barbolini M, Moscetti L, Isca C, Toss A, Barbieri E, Cortesi L, Kaleci S, Maiorana A, Tazzioli G, Cascinu S, Piacentini F. Differential molecular pathways expression in HER2 positive early breast cancer according to hormone receptor status. J Cancer Res Clin Oncol 2019; 145:821-828. [PMID: 30603906 DOI: 10.1007/s00432-018-02833-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 12/21/2018] [Indexed: 01/19/2023]
Abstract
PURPOSE Hormone receptors (HR) status in HER2 + breast cancer (BC) is a recognized stratification factor with relevant clinical implication. According to HR expression, HER2 + BC show different clinical characteristics, treatment sensitivity and prognosis. The interaction between HR and HER2 pathways remains incompletely understood. METHODS Thirty-four HER2 + BC were included: 18 tumors with HER2+/HR + and 16 with HER2+/HR-. The expression of 770 genes and 13 molecular pathways were evaluated using Nanostring PanCancer Pathway panel performed on FFPE BC biopsies. RESULTS Gene expression analysis identified 127 genes with significantly different expression between the two cohorts. 83% of these genes were overexpressed in HER2+/HR- cohort. Globally, 23% of them belonged to PI3K pathway (41 genes), 15% to Trascriptional regulation (26 genes) and 12% to MAPK (22 genes). Regarding pathway expression, PI3K, MAPK and NOTCH were significantly differently expressed between the two groups (p = 0.003, p = 0.0018 and p = 0.02, respectively), all of them were overexpressed in HER2+/HR- tumors. CONCLUSIONS According to HR status, HER2 + tumors express different pathways profiles: the overexpression of PI3K, MAPK and NOTCH pathways in HER2+/HR- group could justify different survival outcomes and treatment sensitivity. The identification of tumor driver pathways may be a useful instrument for individualized pathway-directed therapies. Further clinical implications are warranted.
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Affiliation(s)
- Claudia Omarini
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Via del Pozzo 71, 41122, Modena, Italy.
| | - Stefania Bettelli
- Division of Pathological Anatomy, Department of Diagnostic, Clinical Medicine and Public Health, University Hospital of Modena, Modena, Italy
| | - Cecilia Caprera
- Division of Pathological Anatomy, Department of Diagnostic, Clinical Medicine and Public Health, University Hospital of Modena, Modena, Italy
| | - Samantha Manfredini
- Division of Pathological Anatomy, Department of Diagnostic, Clinical Medicine and Public Health, University Hospital of Modena, Modena, Italy
| | - Monica Barbolini
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Via del Pozzo 71, 41122, Modena, Italy
| | - Luca Moscetti
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Via del Pozzo 71, 41122, Modena, Italy
| | - Chrystel Isca
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Via del Pozzo 71, 41122, Modena, Italy
| | - Angela Toss
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Via del Pozzo 71, 41122, Modena, Italy
| | - Elena Barbieri
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Via del Pozzo 71, 41122, Modena, Italy
| | - Laura Cortesi
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Via del Pozzo 71, 41122, Modena, Italy
| | - Shaniko Kaleci
- Division of Pathological Anatomy, Department of Diagnostic, Clinical Medicine and Public Health, University Hospital of Modena, Modena, Italy
| | - Antonino Maiorana
- Division of Pathological Anatomy, Department of Diagnostic, Clinical Medicine and Public Health, University Hospital of Modena, Modena, Italy
| | - Giovanni Tazzioli
- Oncologic Breast Surgery Unit, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Modena, Italy
| | - Stefano Cascinu
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Via del Pozzo 71, 41122, Modena, Italy
| | - Federico Piacentini
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Via del Pozzo 71, 41122, Modena, Italy
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McDermott MSJ, Conlon N, Browne BC, Szabo A, Synnott NC, O'Brien NA, Duffy MJ, Crown J, O'Donovan N. HER2-Targeted Tyrosine Kinase Inhibitors Cause Therapy-Induced-Senescence in Breast Cancer Cells. Cancers (Basel) 2019; 11:cancers11020197. [PMID: 30743996 PMCID: PMC6406301 DOI: 10.3390/cancers11020197] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 02/01/2019] [Indexed: 01/07/2023] Open
Abstract
Prolonged treatment of HER2 positive breast cancer cells with tyrosine kinase inhibitors (TKIs) leads to the emergence of acquired resistance. However, the effects of continuous TKI exposure on cell fate, and the steps leading to the acquisition of a resistant phenotype are poorly understood. To explore this, we exposed five HER2 positive cells lines to HER2 targeted therapies for periods of up to 4 weeks and examined senescence associated β-galactosidase (SA-β-gal) activity together with additional markers of senescence. We found that lapatinib treatment resulted in phenotypic alterations consistent with a senescent phenotype and strong SA-β-gal activity in HER2-positive cell lines. Lapatinib-induced senescence was associated with elevated levels of p15 and p27 but was not dependent on the expression of p16 or p21. Restoring wild type p53 activity either by transfection or by treatment with APR-246, a molecule which reactivates mutant p53, blocked lapatinib-induced senescence and caused increased cell death. In contrast to lapatinib, SA-β-gal activity was not induced by exposing the cells to trastuzumab as a single agent but co-administration of lapatinib and trastuzumab induced senescence, as did treatment of the cells with the irreversible HER2 TKIs neratinib and afatinib. Neratinib- and afatinib-induced senescence was not reversed by removing the drug whereas lapatinib-induced senescence was reversible. In summary, therapy-induced senescence represents a novel mechanism of action of HER2 targeting agents and may be a potential pathway for the emergence of resistance.
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Affiliation(s)
- Martina S J McDermott
- Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
- Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, 9 Dublin, Ireland.
| | - Neil Conlon
- Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, 9 Dublin, Ireland.
| | - Brigid C Browne
- Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, 9 Dublin, Ireland.
| | - Adam Szabo
- Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, 9 Dublin, Ireland.
| | - Naoise C Synnott
- UCD School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, 4 Dublin, Ireland.
| | - Neil A O'Brien
- Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
| | - Michael J Duffy
- UCD School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, 4 Dublin, Ireland.
- UCD Clinical Research Centre, St. Vincent's University Hospital, 4 Dublin, Ireland.
| | - John Crown
- Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, 9 Dublin, Ireland.
- Department of Medical Oncology, St. Vincent's University Hospital, Elm Park, 4 Dublin, Ireland.
| | - Norma O'Donovan
- Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, 9 Dublin, Ireland.
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Pegram MD, Zong Y, Yam C, Goetz MP, Moulder SL. Innovative Strategies: Targeting Subtypes in Metastatic Breast Cancer. Am Soc Clin Oncol Educ Book 2018; 38:65-77. [PMID: 30231328 DOI: 10.1200/edbk_200715] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Metastatic breast cancer continues to be a life-threatening diagnosis that impacts hundreds of thousands of patients around the world. Targeted therapies are usually associated with less toxicity compared with cytotoxic chemotherapies and often induce response or durable disease control in estrogen receptor (ER) and/or HER2+ breast cancers. Drugs that target CDK 4/6 either alone or in combination with endocrine therapy have demonstrated substantial improvements in progression-free survival (PFS) compared with endocrine monotherapy. Most recently, PARP inhibitors have shown longer PFS compared with physician's choice of chemotherapy in BRCA-associated cancers, leading to the first U.S. Food and Drug Administration (FDA) approval of a targeted therapy with the potential to benefit a subgroup of patients with triple-negative breast cancer (TNBC). Finally, newer drug delivery strategies using antibody drug conjugates have also allowed a "targeted approach" to deliver moderate to extremely potent cytotoxins directly to sites of metastatic disease, with less toxicity.
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Affiliation(s)
- Mark D Pegram
- From the Stanford Comprehensive Cancer, Stanford, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; Mayo Clinic Cancer Center, Rochester, MN
| | - Yu Zong
- From the Stanford Comprehensive Cancer, Stanford, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; Mayo Clinic Cancer Center, Rochester, MN
| | - Clinton Yam
- From the Stanford Comprehensive Cancer, Stanford, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; Mayo Clinic Cancer Center, Rochester, MN
| | - Matthew P Goetz
- From the Stanford Comprehensive Cancer, Stanford, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; Mayo Clinic Cancer Center, Rochester, MN
| | - Stacy L Moulder
- From the Stanford Comprehensive Cancer, Stanford, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; Mayo Clinic Cancer Center, Rochester, MN
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Arannilewa1 AJ, Suleiman Alakanse O, Adesola AO, Israel Malachi O, Michael Obaidu I, Oluwafemi EE, Damilola Afolayan E, Folakemi Afere P, Abdullateef Ayuba K, Oluwafemi Bolarinwa T, Oche Ambrose G. Molecular docking analysis of Cianidanol fromGinkgo biloba with HER2+ breast cancer target. Bioinformation 2018; 14:482-487. [PMID: 31223207 PMCID: PMC6563659 DOI: 10.6026/97320630014482] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 10/08/2018] [Accepted: 10/09/2018] [Indexed: 12/18/2022] Open
Abstract
HER2 is a known therapeutic target for about 30% of breast cancer patients where HER2 is over expressed and this is referred to as HER2 positive breast cancer. This subtype is characterized by a clinical behavior know to be especially aggressive. Improved HER2 targeting agents such as trastuzumab, pertuzumb, lapatinib and ado-trastuzumab emtansine are available. Some patients have shown no response to treatment while others show progress to these agents. Therefore, it is of interest to screen HER2+ with phyto-chemical lead compound from Ginkgo biloba using molecular docking techniques. We screened 25 phyto-chemicals from literature with HER2+. Results show that cianidanol have an acceptable binding energy of (-8.2kcal/mol). Thus, we report the binding properties of cianidanol with HER2+.
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Affiliation(s)
- Abiodun Julius Arannilewa1
- Department of Biochemistry, University of Ilorin, Ilorin, Nigeria
- Department of Biochemistry, Ekiti State University, Ado Ekiti,Nigeria
| | | | | | | | - Ifedayo Michael Obaidu
- Department of Biochemistry, Ekiti State University, Ado Ekiti,Nigeria
- Department ofBiochemistry, University of Ibadan, Ibadan, Nigeria
| | | | | | - Patricia Folakemi Afere
- Department of Biochemistry, University of Ilorin, Ilorin, Nigeria
- Department of Biochemistry, Federal University of Technology, Akure, Nigeria
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Ding Y, Gong C, Huang D, Chen R, Sui P, Lin KH, Liang G, Yuan L, Xiang H, Chen J, Yin T, Alexander PB, Wang QF, Song EW, Li QJ, Wood KC, Wang XF. Synthetic lethality between HER2 and transaldolase in intrinsically resistant HER2-positive breast cancers. Nat Commun 2018; 9:4274. [PMID: 30323337 PMCID: PMC6189078 DOI: 10.1038/s41467-018-06651-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 09/13/2018] [Indexed: 12/13/2022] Open
Abstract
Intrinsic resistance to anti-HER2 therapy in breast cancer remains an obstacle in the clinic, limiting its efficacy. However, the biological basis for intrinsic resistance is poorly understood. Here we performed a CRISPR/Cas9-mediated loss-of-function genetic profiling and identified TALDO1, which encodes the rate-limiting transaldolase (TA) enzyme in the non-oxidative pentose phosphate pathway, as essential for cellular survival following pharmacological HER2 blockade. Suppression of TA increases cell susceptibility to HER2 inhibition in two intrinsically resistant breast cancer cell lines with HER2 amplification. Mechanistically, TA depletion combined with HER2 inhibition significantly reduces cellular NADPH levels, resulting in excessive ROS production and deficient lipid and nucleotide synthesis. Importantly, higher TA expression correlates with poor response to HER2 inhibition in a breast cancer patient cohort. Together, these results pinpoint TA as a novel metabolic enzyme possessing synthetic lethality with HER2 inhibition that can potentially be exploited as a biomarker or target for combination therapy. Resistance to anti-HER2 therapy in breast cancer remains a major obstacle in the clinic. Here the authors performed a CRISPR-selective vulnerability screen to identify transaldoloase as a target that is synthetically lethal with HER2 inhibition in breast cancer cells.
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Affiliation(s)
- Yi Ding
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27705, USA
| | - Chang Gong
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - De Huang
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27705, USA
| | - Rui Chen
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27705, USA
| | - Pinpin Sui
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Kevin H Lin
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27705, USA
| | - Gehao Liang
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Lifeng Yuan
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27705, USA
| | - Handan Xiang
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27705, USA
| | - Junying Chen
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Tao Yin
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27705, USA
| | - Peter B Alexander
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27705, USA
| | - Qian-Fei Wang
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Er-Wei Song
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Qi-Jing Li
- Department of Immunology, Duke University Medical Center, Durham, NC, 27705, USA
| | - Kris C Wood
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27705, USA.
| | - Xiao-Fan Wang
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27705, USA.
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Eustace AJ, Conlon NT, McDermott MSJ, Browne BC, O'Leary P, Holmes FA, Espina V, Liotta LA, O'Shaughnessy J, Gallagher C, O'Driscoll L, Rani S, Madden SF, O'Brien NA, Ginther C, Slamon D, Walsh N, Gallagher WM, Zagozdzon R, Watson WR, O'Donovan N, Crown J. Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL. BMC Cancer 2018; 18:965. [PMID: 30305055 PMCID: PMC6180577 DOI: 10.1186/s12885-018-4852-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 09/24/2018] [Indexed: 12/30/2022] Open
Abstract
Background Lapatinib has clinical efficacy in the treatment of trastuzumab-refractory HER2-positive breast cancer. However, a significant proportion of patients develop progressive disease due to acquired resistance to the drug. Induction of apoptotic cell death is a key mechanism of action of lapatinib in HER2-positive breast cancer cells. Methods We examined alterations in regulation of the intrinsic and extrinsic apoptosis pathways in cell line models of acquired lapatinib resistance both in vitro and in patient samples from the NCT01485926 clinical trial, and investigated potential strategies to exploit alterations in apoptosis signalling to overcome lapatinib resistance in HER2-positive breast cancer. Results In this study, we examined two cell lines models of acquired lapatinib resistance (SKBR3-L and HCC1954-L) and showed that lapatinib does not induce apoptosis in these cells. We identified alterations in members of the BCL-2 family of proteins, in particular MCL-1 and BAX, which may play a role in resistance to lapatinib. We tested the therapeutic inhibitor obatoclax, which targets MCL-1. Both SKBR3-L and HCC1954-L cells showed greater sensitivity to obatoclax-induced apoptosis than parental cells. Interestingly, we also found that the development of acquired resistance to lapatinib resulted in acquired sensitivity to TRAIL in SKBR3-L cells. Sensitivity to TRAIL in the SKBR3-L cells was associated with reduced phosphorylation of AKT, increased expression of FOXO3a and decreased expression of c-FLIP. In SKBR3-L cells, TRAIL treatment caused activation of caspase 8, caspase 9 and caspase 3/7. In a second resistant model, HCC1954-L cells, p-AKT levels were not decreased and these cells did not show enhanced sensitivity to TRAIL. Furthermore, combining obatoclax with TRAIL improved response in SKBR3-L cells but not in HCC1954-L cells. Conclusions Our findings highlight the possibility of targeting altered apoptotic signalling to overcome acquired lapatinib resistance, and identify potential novel treatment strategies, with potential biomarkers, for HER2-positive breast cancer that is resistant to HER2 targeted therapies. Electronic supplementary material The online version of this article (10.1186/s12885-018-4852-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Alex J Eustace
- Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.
| | - Neil T Conlon
- Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland
| | - Martina S J McDermott
- Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland
| | - Brigid C Browne
- Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland
| | - Patrick O'Leary
- UCD School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Frankie A Holmes
- Texas Oncology-Memorial Hermann Memorial City, US Oncology Research, 925 Gessner Road #550, Houston, TX, 77024-2546, USA
| | | | | | | | - Clair Gallagher
- Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland
| | - Lorraine O'Driscoll
- School of Pharmacy & Pharmaceutical Sciences, and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Sweta Rani
- School of Pharmacy & Pharmaceutical Sciences, and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Stephen F Madden
- Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.,Data Science Centre, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Neil A O'Brien
- Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, California, Los Angeles, USA
| | - Charles Ginther
- Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, California, Los Angeles, USA
| | - Dennis Slamon
- Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, California, Los Angeles, USA
| | - Naomi Walsh
- Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland
| | - William M Gallagher
- UCD School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Radoslaw Zagozdzon
- Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, Nowogrodzka, 59, Warsaw, Poland
| | - William R Watson
- UCD School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Norma O'Donovan
- Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland
| | - John Crown
- Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.,Department of Oncology, St. Vincent's University Hospital, Dublin, Ireland
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Sudhan DR, Schwarz LJ, Guerrero-Zotano A, Formisano L, Nixon MJ, Croessmann S, González Ericsson PI, Sanders M, Balko JM, Avogadri-Connors F, Cutler RE, Lalani AS, Bryce R, Auerbach A, Arteaga CL. Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER +/HER2 + Breast Cancers: Implications to the ExteNET Trial. Clin Cancer Res 2018; 25:771-783. [PMID: 30274983 DOI: 10.1158/1078-0432.ccr-18-1131] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 08/09/2018] [Accepted: 09/26/2018] [Indexed: 11/16/2022]
Abstract
PURPOSE The phase III ExteNET trial showed improved invasive disease-free survival in patients with HER2+ breast cancer treated with neratinib versus placebo after trastuzumab-based adjuvant therapy. The benefit from neratinib appeared to be greater in patients with ER+/HER2+ tumors. We thus sought to discover mechanisms that may explain the benefit from extended adjuvant therapy with neratinib.Experimental Design: Mice with established ER+/HER2+ MDA-MB-361 tumors were treated with paclitaxel plus trastuzumab ± pertuzumab for 4 weeks, and then randomized to fulvestrant ± neratinib treatment. The benefit from neratinib was evaluated by performing gene expression analysis for 196 ER targets, ER transcriptional reporter assays, and cell-cycle analyses. RESULTS Mice receiving "extended adjuvant" therapy with fulvestrant/neratinib maintained a complete response, whereas those treated with fulvestrant relapsed rapidly. In three ER+/HER2+ cell lines (MDA-MB-361, BT-474, UACC-893) but not in ER+/HER2- MCF7 cells, treatment with neratinib induced ER reporter transcriptional activity, whereas treatment with fulvestrant resulted in increased HER2 and EGFR phosphorylation, suggesting compensatory reciprocal crosstalk between the ER and ERBB RTK pathways. ER transcriptional reporter assays, gene expression, and immunoblot analyses showed that treatment with neratinib/fulvestrant, but not fulvestrant, potently inhibited growth and downregulated ER reporter activity, P-AKT, P-ERK, and cyclin D1 levels. Finally, similar to neratinib, genetic and pharmacologic inactivation of cyclin D1 enhanced fulvestrant action against ER+/HER2+ breast cancer cells. CONCLUSIONS These data suggest that ER blockade leads to reactivation of ERBB RTKs and thus extended ERBB blockade is necessary to achieve durable clinical outcomes in patients with ER+/HER2+ breast cancer.
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Affiliation(s)
- Dhivya R Sudhan
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Luis J Schwarz
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.,Oncosalud-AUNA, Lima, Peru
| | - Angel Guerrero-Zotano
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Luigi Formisano
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Mellissa J Nixon
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Sarah Croessmann
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Paula I González Ericsson
- Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Melinda Sanders
- Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.,Department of Pathology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Justin M Balko
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.,Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.,Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | | | | | | | | | | | - Carlos L Arteaga
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. .,Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.,Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.,Harold C. Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas
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Phosphoproteomic analysis reveals PAK2 as a therapeutic target for lapatinib resistance in HER2-positive breast cancer cells. Biochem Biophys Res Commun 2018; 505:187-193. [PMID: 30243723 DOI: 10.1016/j.bbrc.2018.09.086] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 09/02/2018] [Accepted: 09/13/2018] [Indexed: 11/24/2022]
Abstract
The human epidermal growth factor receptor 2 (HER2)-positive breast cancer with overexpression of HER2 accounts for approximately 25% of breast cancers and is more aggressive than other types of breast cancer. Lapatinib has been widely used as a HER2-targeted therapy, however, a number of patients develop lapatinib resistance and still suffer from poor prognosis. Therefore, it is essential to identify novel therapeutic targets that could overcome lapatinib resistance. In this study, we carried out phosphoproteomic analysis of lapatinib sensitive and resistant cell lines (SKBR3 and SKBR3-LR) using stable isotope labeling with amino acids in cell culture (SILAC). We identified 3808 phosphopeptides from 1807 proteins and then analyzed signaling pathways, Gene Ontology, and protein-protein interaction networks. Finally, we identified PAK2 as a therapeutic target from the network analysis and validated that PAK2 knockdown and PAK inhibitor treatment resensitize the lapatinib resistant cells to lapatinib. This results suggest that PAK2 is a potent therapeutic target to overcome acquired lapatinib resistance in HER2-positive breast cancer cells.
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49
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Soto-Perez-De-Celis E, Loh KP, Baldini C, Battisti NML, Chavarri-Guerra Y, De Glas NA, Hsu T, Hurria A. Targeted agents for HER2-positive breast cancer in older adults: current and future perspectives. Expert Opin Investig Drugs 2018; 27:787-801. [PMID: 30196727 DOI: 10.1080/13543784.2018.1520838] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION One-third of breast cancer (BC) cases worldwide occur in women aged 65 years and older, with 10 to 15% overexpressing the human epidermal growth factor receptor 2 (HER2). Although several HER2-targeted therapies have been developed, the lack of data regarding their use in older patients hampers evidence-based decision-making for this population. AREAS COVERED We review current evidence on the efficacy and safety of HER2-targeted therapies in older adults with BC, focusing on approved therapies such as trastuzumab, lapatinib, pertuzumab, ado-trastuzumab-emtansine, and neratinib. Additionally, we discuss drugs under development to target the HER2-receptor, and to overcome resistance to existing therapies. Finally, we highlight the cardiotoxicity of HER2-targeted drugs among older adults. EXPERT OPINION Older adults are underrepresented in trials of HER2-targeted therapies in BC. We propose strategies to increase recruitment of older adults in clinical trials in order to increase the evidence base to treat this growing population.
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Affiliation(s)
- Enrique Soto-Perez-De-Celis
- a Department of Geriatrics , Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran , Mexico City , Mexico
| | - Kah Poh Loh
- b Division of Hematology/Oncology, Department of Medicine , University of Rochester School of Medicine and Dentistry/James P. Wilmot Cancer Center , Rochester , NY , USA
| | - Capucine Baldini
- c Drug Development Department (DITEP) , Gustave Roussy Cancer Campus , Villejuif , France
| | | | - Yanin Chavarri-Guerra
- e Department of Hemato-Oncology , Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran , Mexico City , Mexico
| | - Nienke A De Glas
- f Department of Surgery , Leiden University Medical Center , Leiden , Netherlands
| | - Tina Hsu
- g Division of Medical Oncology , The Ottawa Hospital Cancer Centre, University of Ottawa , Ottawa , Canada
| | - Arti Hurria
- h Center for Cancer and Aging , City of Hope , Duarte , CA , USA
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50
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Rusz O, Kószó R, Dobi Á, Csenki M, Valicsek E, Nikolényi A, Uhercsák G, Cserháti A, Kahán Z. Clinical benefit of fulvestrant monotherapy in the multimodal treatment of hormone receptor and HER2 positive advanced breast cancer: a case series. Onco Targets Ther 2018; 11:5459-5463. [PMID: 30233207 PMCID: PMC6129034 DOI: 10.2147/ott.s170736] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Fulvestrant is a pure estrogen receptor (ER) antagonist approved for the treatment of metastatic ER positive breast cancer in postmenopausal women with disease progression following antiestrogen therapy. The clinical results of fulvestrant demonstrated encouraging activity in tumors in spite of HER2 positivity, but data about its use after progression on anti-HER2 agents are limited. Partial responses and durations of response of 12, 25, and 38 months in three cases with multiple metastases of ER positive and HER2 positive breast cancer were observed; all patients had been treated with 1–4 regimens of an anti-HER2 agent in combination with chemotherapy or an aromatase inhibitor before the initiation of fulvestrant. Fulvestrant is a valuable option with limited toxicity and durable response in metastatic HER2 and ER positive breast cancer after progression on anti-HER2 agents as well. Therapeutic benefit even in extensive skin metastases and (irradiated) brain metastases may be expected. Further investigations are warranted to establish where it fits into the multimodal management of ER and HER positive breast cancer.
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Affiliation(s)
- Orsolya Rusz
- Department of Oncotherapy, University of Szeged, Szeged, Hungary,
| | - Renáta Kószó
- Department of Oncotherapy, University of Szeged, Szeged, Hungary,
| | - Ágnes Dobi
- Department of Oncotherapy, University of Szeged, Szeged, Hungary,
| | - Melinda Csenki
- Department of Oncotherapy, University of Szeged, Szeged, Hungary,
| | | | - Alíz Nikolényi
- Department of Oncotherapy, University of Szeged, Szeged, Hungary,
| | | | | | - Zsuzsanna Kahán
- Department of Oncotherapy, University of Szeged, Szeged, Hungary,
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