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Asnaghi R, Antonarelli G, Battaiotto E, Castellano G, Guidi L, Izzo D, Zagami P, Trapani D, Curigliano G. An update on promising and emerging protein kinase B/AKT inhibitors for breast cancer. Expert Opin Pharmacother 2025; 26:235-247. [PMID: 39846444 DOI: 10.1080/14656566.2025.2454290] [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: 11/07/2024] [Revised: 01/10/2025] [Accepted: 01/13/2025] [Indexed: 01/24/2025]
Abstract
INTRODUCTION The PI3K pathway is crucial in breast cancer (BC), influencing cell survival, growth, and metabolism, with AKT playing a central role in treatment resistance. This pathway's involvement in breast carcinogenesis and its link to treatment resistance underscores the significance of targeting it in BC therapy. PI3K-pathway inhibitors offer new therapeutic avenues but bring challenges, especially due to toxicity issues that hinder their development. AREAS COVERED This review discusses the PI3K-pathway inhibitors used in BC, highlighting emerging, innovative strategies. EXPERT OPINION The introduction of mTOR inhibitors marked a key step in tackling hormone receptor-positive (HR+) BC, targeting endocrine resistance. However, toxicity concerns remain, especially with PIK3CA and AKT inhibitors. Selective PI3K-targeted agents aim to reduce off-target toxicity, enhancing patient adherence and control over the disease. New compounds employing allosteric mechanisms may further limit adverse effects and allow safer combination therapies, previously limited by toxicity. Advancements in dosing strategies focus on patient-centered outcomes, and synergistic agents are essential in advancing AKT-pathway inhibition, paving the way for a new phase in HR+ BC treatment.
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Affiliation(s)
- Riccardo Asnaghi
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Gabriele Antonarelli
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Elena Battaiotto
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Grazia Castellano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Lorenzo Guidi
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Davide Izzo
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Paola Zagami
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Dario Trapani
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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Mehta K, Hegde M, Girisa S, Vishwa R, Alqahtani MS, Abbas M, Shakibaei M, Sethi G, Kunnumakkara AB. Targeting RTKs/nRTKs as promising therapeutic strategies for the treatment of triple-negative breast cancer: evidence from clinical trials. Mil Med Res 2024; 11:76. [PMID: 39668367 PMCID: PMC11636053 DOI: 10.1186/s40779-024-00582-z] [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: 10/19/2023] [Accepted: 11/08/2024] [Indexed: 12/14/2024] Open
Abstract
The extensive heterogeneity and the limited availability of effective targeted therapies contribute to the challenging prognosis and restricted survival observed in triple-negative breast cancer (TNBC). Recent research indicates the aberrant expression of diverse tyrosine kinases (TKs) within this cancer, contributing significantly to tumor cell proliferation, survival, invasion, and migration. The contemporary paradigm shift towards precision medicine has highlighted TKs and their receptors as promising targets for pharmacotherapy against a range of malignancies, given their pivotal roles in tumor initiation, progression, and advancement. Intensive investigations have focused on various monoclonal antibodies (mAbs) and small molecule inhibitors that specifically target proteins such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), cellular mesenchymal-epithelial transition factor (c-MET), human epidermal growth factor receptor 2 (HER2), among others, for combating TNBC. These agents have been studied both in monotherapy and in combination with other chemotherapeutic agents. Despite these advances, a substantial terrain of unexplored potential lies within the realm of TK targeted therapeutics, which hold promise in reshaping the therapeutic landscape. This review summarizes the various TK targeted therapeutics that have undergone scrutiny as potential therapeutic interventions for TNBC, dissecting the outcomes and revelations stemming from diverse clinical investigations. A key conclusion from the umbrella clinical trials evidences the necessity for in-depth molecular characterization of TNBCs for the maximum efficiency of TK targeted therapeutics, either as standalone treatments or a combination. Moreover, our observation highlights that the outcomes of TK targeted therapeutics in TNBC are substantially influenced by the diversity of the patient cohort, emphasizing the prioritization of individual patient genetic/molecular profiles for precise TNBC patient stratification for clinical studies.
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Affiliation(s)
- Kasshish Mehta
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Ravichandran Vishwa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, 61421, Abha, Saudi Arabia
- BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester, LE1 7RH, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, 61421, Abha, Saudi Arabia
| | - Mehdi Shakibaei
- Department of Human-Anatomy, Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Ludwig-Maximilian-University, 80336, Munich, Germany
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117699, Singapore.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India.
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Wang Z, Lu H, Zhong Y, Feng L, Jin H, Wang X. Impaired cyclin D3 protein degradation contributes to trastuzumab resistance in HER2 positive breast cancer. Med Oncol 2024; 41:305. [PMID: 39487929 PMCID: PMC11531418 DOI: 10.1007/s12032-024-02535-x] [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: 08/26/2024] [Accepted: 10/05/2024] [Indexed: 11/04/2024]
Abstract
As the first anti-HER2 targeted agent approved by FDA in 1998, Trastuzumab has significantly improved the outcome of patients with HER2 positive metastatic breast cancer. Unfortunately, resistance to trastuzumab is a severe obstacle to its therapeutic efficacy in clinical application, and its mechanism has not yet been fully elucidated. In our study, we found that stabilization of cyclin D3 could be one reason for trastuzumab resistance. Trastuzumab could induce G1/G0 phase arrest by downregulating cyclin D3 protein expression. However, the protein expression of cyclin D3 was not affected in trastuzumab-resistant cells, which might be related to aberrant activation of ERK signaling pathway. Furthermore, degradation of cyclin D3 protein by trastuzumab was mainly resulted from ubiquitin-dependent proteasome mechanism instead of transcriptional regulation. In trastuzumab-resistant breast cancer cells, trastuzumab-induced degradation of cyclin D3 protein was abrogated. When the ubiquitin pathway was inhibited, cells would show a predisposition to resistance to trastuzumab. Further, CDK4/6 inhibitor can inhibit the proliferation of trastuzumab-resistant HER-2 positive breast cancer cells. Therefore, combination of CDK4/6 inhibitors and anti-HER2 targeted therapy may be an alternative and promising strategy to overcome trastuzumab resistance in the future.
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Affiliation(s)
- Zhuo Wang
- Department of Medical Oncology, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
- Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Haiqi Lu
- Department of Medical Oncology, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
- Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yiming Zhong
- Department of Medical Oncology, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
- Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lifeng Feng
- Department of Medical Oncology, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
- Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hongchuan Jin
- Department of Medical Oncology, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
- Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xian Wang
- Department of Medical Oncology, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China.
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Zheng S, Chen R, Zhang L, Tan L, Li L, Long F, Wang T. Unraveling the future: Innovative design strategies and emerging challenges in HER2-targeted tyrosine kinase inhibitors for cancer therapy. Eur J Med Chem 2024; 276:116702. [PMID: 39059182 DOI: 10.1016/j.ejmech.2024.116702] [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: 06/14/2024] [Revised: 07/12/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024]
Abstract
Human epidermal growth factor receptor 2 (HER2) is a transmembrane receptor-like protein with tyrosine kinase activity that plays a vital role in processes such as cell proliferation, differentiation, and angiogenesis. The degree of malignancy of different cancers, notably breast cancer, is strongly associated with HER2 amplification, overexpression, and mutation. Currently, widely used clinical HER2 tyrosine kinase inhibitors (TKIs), such as lapatinib and neratinib, have several drawbacks, including susceptibility to drug resistance caused by HER2 mutations and adverse effects from insufficient HER2 selectivity. To address these issues, it is essential to create innovative HER2 TKIs with enhanced safety, effectiveness against mutations, and high selectivity. Typically, SPH5030 has advanced to phase I clinical trials for its strong suppression of four HER2 mutations. This review discusses the latest research progress in HER2 TKIs, with a focus on the structural optimization process and structure-activity relationship analysis. In particular, this study highlights promising design strategies to address these challenges, providing insightful information and inspiration for future development in this field.
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Affiliation(s)
- Sixiang Zheng
- Department of Clinical Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Ruixian Chen
- Department of Breast Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lele Zhang
- Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Lun Tan
- Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Lintao Li
- Department of Radiotherapy, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China.
| | - Fangyi Long
- Laboratory Medicine Center, Sichuan Provincial Maternity and Child Health Care Hospital, Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, 610032, China.
| | - Ting Wang
- Department of Clinical Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, 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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Blasquez L, Bouzinba‐Segard H, Bourdoulous S, Faure C. Ebselen oxide and derivatives are new allosteric HER2 inhibitors for HER2-positive cancers. Mol Oncol 2023; 17:1981-1999. [PMID: 36912768 PMCID: PMC10552892 DOI: 10.1002/1878-0261.13419] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 02/07/2023] [Accepted: 03/10/2023] [Indexed: 03/14/2023] Open
Abstract
Human epidermal growth factor receptor 2 (ErbB2/HER2) is a tyrosine kinase receptor that is overexpressed in 25% of primary human breast cancers, as well as in multiple other cancers. HER2-targeted therapies improved progression-free and overall survival in patients with HER2+ breast cancers. However, associated resistance mechanisms and toxicity highlight the need for new therapeutic approaches for these cancers. We recently established that, in normal cells, HER2 is stabilized in a catalytically repressed state by direct interaction with members of the ezrin/radixin/moesin (ERM) family. In HER2-overexpressing tumors, the low expression of moesin contributes to the aberrant activation of HER2. Through a screen designed to find moesin-mimicking compounds, we identified ebselen oxide. We show that ebselen oxide, and some derivatives, conferred an efficient allosteric inhibition of overexpressed HER2, as well as mutated and truncated oncogenic forms of HER2, which are resistant to current therapies. Ebselen oxide selectively inhibited anchorage-dependent and -independent proliferation of HER2+ cancer cells and showed a significant benefit in combination with current anti-HER2 therapeutic agents. Finally, ebselen oxide significantly blocked HER2+ breast tumor progression in vivo. Collectively, these data provide evidence that ebselen oxide is a newly identified allosteric inhibitor of HER2 to be considered for therapeutic intervention on HER2+ cancers.
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Affiliation(s)
- Lucas Blasquez
- Université Paris Cité, CNRS, INSERM, Institut CochinParisFrance
| | | | | | - Camille Faure
- Université Paris Cité, CNRS, INSERM, Institut CochinParisFrance
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Yin L, Chen GL, Xiang Z, Liu YL, Li XY, Bi JW, Wang Q. Current progress in chimeric antigen receptor-modified T cells for the treatment of metastatic breast cancer. Biomed Pharmacother 2023; 162:114648. [PMID: 37023621 DOI: 10.1016/j.biopha.2023.114648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/30/2023] [Accepted: 03/31/2023] [Indexed: 04/07/2023] Open
Abstract
Breast cancer is the leading cancer in women. Around 20-30% breast cancer patients undergo invasion or metastasis after radical surgical resection and eventually die. Number of breast cancer patients show poor sensitivity toward treatments despite the advances in chemotherapy, endocrine therapy, and molecular targeted treatments. Therapeutic resistance and tumor recurrence or metastasis develop with the ongoing treatments. Conducive treatment strategies are thus required. Chimeric antigen receptor (CAR)-modified T-cell therapy has progressed as a part of tumor immunotherapy. However, CAR-T treatment has not been effective in solid tumors because of tumor microenvironment complexity, inhibitory effects of extracellular matrix, and lacking ideal tumor antigens. Herein, the prospects of CAR-T cell therapy for metastatic breast cancer are discussed, and the targets for CAR-T therapy in breast cancer (HER-2, C-MET, MSLN, CEA, MUC1, ROR1, EGFR) at clinical level are reviewed. Moreover, solutions are proposed for the challenges of breast cancer CAR-T therapy regarding off-target effects, heterogeneous antigen expression by tumor cells and immunosuppressive tumor microenvironment. Ideas for improving the therapeutics of CAR-T cell therapy in metastatic breast cancer are suggested.
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Affiliation(s)
- Li Yin
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China; Shandong University of Traditional Chinese Medicine, 250355 Jinan, China
| | - Gui-Lai Chen
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China
| | - Zhuo Xiang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China
| | - Yu-Lin Liu
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China
| | - Xing-Yu Li
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 266003 Qingdao, China
| | - Jing-Wang Bi
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China.
| | - Qiang Wang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China; Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 266003 Qingdao, China.
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Chow CY, Lie EF, Wu CH, Chow LW. Clinical implication of genetic composition and molecular mechanism on treatment strategies of HER2-positive breast cancers. Front Oncol 2022; 12:964824. [PMID: 36387174 PMCID: PMC9659858 DOI: 10.3389/fonc.2022.964824] [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: 06/09/2022] [Accepted: 10/14/2022] [Indexed: 12/01/2022] Open
Abstract
The current clinical management model of HER2-positive breast cancers is commonly based on guidelines, which in turn are based on the design and outcome of clinical trials. While this model is useful to most practicing clinicians, the treatment outcome of individual patient is not certain at the start of treatment. As the understanding of the translational research of carcinogenesis and the related changes in cancer genetics and tumor microenvironment during treatment is critical in the selection of right choice of treatment to maximize the successful clinical outcome for the patient, this review article intends to discuss the latest developments in the genetic and molecular mechanisms of cancer progression and treatment resistance, and how they influence the planning of the treatment strategies of HER2-positive breast cancers.
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Affiliation(s)
- Christopher Y.C. Chow
- UNIMED Medical Institute, Hong Kong, Hong Kong SAR, China
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | | | - Cheng-Hsun Wu
- Department of Anatomy, China Medical University, Taichung, Taiwan
| | - Louis W.C. Chow
- UNIMED Medical Institute, Hong Kong, Hong Kong SAR, China
- Organisation for Oncology and Translational Research, Hong Kong, Hong Kong SAR, China
- *Correspondence: Louis W.C. Chow,
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Dorraji E, Borgen E, Segura-Peña D, Rawat P, Smorodina E, Dunn C, Greiff V, Sekulić N, Russnes H, Kyte JA. Development of a High-Affinity Antibody against the Tumor-Specific and Hyperactive 611-p95HER2 Isoform. Cancers (Basel) 2022; 14:cancers14194859. [PMID: 36230782 PMCID: PMC9563779 DOI: 10.3390/cancers14194859] [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: 09/03/2022] [Revised: 09/29/2022] [Accepted: 09/30/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary In the present study, we addressed the unmet need for a molecular antibody (mAb) with high affinity and specificity against a truncated hyperactive isoform of human epidermal growth factor receptor 2 (HER2), called 611-carboxy terminal fragment (CTF)-p95HER2. Patients with p95HER2+ breast cancer are at risk of developing metastatic breast cancer with a poor prognosis and resistance to therapies targeting full-length HER2. We have generated a mAb named Oslo-2, which react specifically with 611-CTF-p95HER2 and has a high affinity. We also characterized the antigenic determinant (epitope) on the p95HER2 protein and the antigen-binding site (paratope) on the Oslo-2 mAb. The antibody can be used to develop antibody- or cell-based therapies targeting p95HER2, as well as a diagnostic assay to identify p95HER2+ disease. Abstract The expression of human epidermal growth factor receptor 2 (HER2) is a key classification factor in breast cancer. Many breast cancers express isoforms of HER2 with truncated carboxy-terminal fragments (CTF), collectively known as p95HER2. A common p95HER2 isoform, 611-CTF, is a biomarker for aggressive disease and confers resistance to therapy. Contrary to full-length HER2, 611-p95HER2 has negligible normal tissue expression. There is currently no approved diagnostic assay to identify this subgroup and no therapy targeting this mechanism of tumor escape. The purpose of this study was to develop a monoclonal antibody (mAb) against 611-CTF-p95HER2. Hybridomas were generated from rats immunized with cells expressing 611-CTF. A hybridoma producing a highly specific Ab was identified and cloned further as a mAb. This mAb, called Oslo-2, gave strong staining for 611-CTF and no binding to full-length HER2, as assessed in cell lines and tissues by flow cytometry, immunohistochemistry and immunofluorescence. No cross-reactivity against HER2 negative controls was detected. Surface plasmon resonance analysis demonstrated a high binding affinity (equilibrium dissociation constant 2 nM). The target epitope was identified at the N-terminal end, using experimental alanine scanning. Further, the mAb paratope was identified and characterized with hydrogen-deuterium-exchange, and a molecular model for the (Oslo-2 mAb:611-CTF-p95HER2) complex was generated by an experimental-information-driven docking approach. We conclude that the Oslo-2 mAb has a high affinity and is highly specific for 611-CTF-p95HER2. The Ab may be used to develop potent and safe therapies, overcoming p95HER2-mediated tumor escape, as well as for developing diagnostic assays.
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Affiliation(s)
- Esmaeil Dorraji
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway
| | - Elin Borgen
- Department of Pathology, Oslo University Hospital, 0379 Oslo, Norway
| | - Dario Segura-Peña
- Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, Faculty of Medicine, University of Oslo, 0318 Oslo, Norway
| | - Puneet Rawat
- Department of Immunology, University of Oslo and Oslo University Hospital, 0372 Oslo, Norway
| | - Eva Smorodina
- Department of Immunology, University of Oslo and Oslo University Hospital, 0372 Oslo, Norway
| | - Claire Dunn
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway
| | - Victor Greiff
- Department of Immunology, University of Oslo and Oslo University Hospital, 0372 Oslo, Norway
| | - Nikolina Sekulić
- Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, Faculty of Medicine, University of Oslo, 0318 Oslo, Norway
- Department of Chemistry, University of Oslo, 0371 Oslo, Norway
| | - Hege Russnes
- Department of Pathology, Oslo University Hospital, 0379 Oslo, Norway
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway
| | - Jon Amund Kyte
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway
- Department of Clinical Cancer Research, Oslo University Hospital, 0379 Oslo, Norway
- Correspondence:
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Maddox AL, Brehove MS, Eliato KR, Saftics A, Romano E, Press MF, Mortimer J, Jones V, Schmolze D, Seewaldt VL, Jovanovic-Talisman T. Molecular Assessment of HER2 to Identify Signatures Associated with Therapy Response in HER2-Positive Breast Cancer. Cancers (Basel) 2022; 14:2795. [PMID: 35681773 PMCID: PMC9179327 DOI: 10.3390/cancers14112795] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/29/2022] [Accepted: 06/01/2022] [Indexed: 11/16/2022] Open
Abstract
Trastuzumab, the prototype HER2-directed therapy, has markedly improved survival for women with HER2-positive breast cancers. However, only 40-60% of women with HER2-positive breast cancers achieve a complete pathological response to chemotherapy combined with HER2-directed therapy. The current diagnostic assays have poor positive-predictive accuracy in identifying therapy-responsive breast cancers. Here, we deployed quantitative single molecule localization microscopy to assess the molecular features of HER2 in a therapy-responsive setting. Using fluorescently labeled trastuzumab as a probe, we first compared the molecular features of HER2 in trastuzumab-sensitive (BT-474 and SK-BR-3) and trastuzumab-resistant (BT-474R and JIMT-1) cultured cell lines. Trastuzumab-sensitive cells had significantly higher detected HER2 densities and clustering. We then evaluated HER2 in pre-treatment core biopsies from women with breast cancer undergoing neoadjuvant therapy. A complete pathological response was associated with a high detected HER2 density and significant HER2 clustering. These results established the nano-organization of HER2 as a potential signature of therapy-responsive disease.
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Affiliation(s)
- Adam L. Maddox
- Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (A.L.M.); (M.S.B.); (K.R.E.); (A.S.); (E.R.)
| | - Matthew S. Brehove
- Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (A.L.M.); (M.S.B.); (K.R.E.); (A.S.); (E.R.)
| | - Kiarash R. Eliato
- Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (A.L.M.); (M.S.B.); (K.R.E.); (A.S.); (E.R.)
| | - Andras Saftics
- Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (A.L.M.); (M.S.B.); (K.R.E.); (A.S.); (E.R.)
| | - Eugenia Romano
- Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (A.L.M.); (M.S.B.); (K.R.E.); (A.S.); (E.R.)
| | - Michael F. Press
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA;
| | - Joanne Mortimer
- Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
| | - Veronica Jones
- Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
| | - Daniel Schmolze
- Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
| | - Victoria L. Seewaldt
- Department of Population Sciences, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
| | - Tijana Jovanovic-Talisman
- Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (A.L.M.); (M.S.B.); (K.R.E.); (A.S.); (E.R.)
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11
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Kedashiro S, Kameyama T, Mizutani K, Takai Y. Stimulatory role of nectin-4 and p95-ErbB2 in multilayered T47D cell proliferation. Genes Cells 2022; 27:451-464. [PMID: 35430770 DOI: 10.1111/gtc.12940] [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: 04/01/2022] [Revised: 04/11/2022] [Accepted: 04/11/2022] [Indexed: 11/29/2022]
Abstract
Multilayered proliferation in an adherent culture as well as proliferation in a suspension culture is a characteristic feature of cancer cells. We previously showed using T47D human mammary cancer cells that nectin-4, upregulated in many cancer cells, cis-interacts with ErbB2 and its trastuzumab-resistant splice variants, p95-ErbB2 and ErbB2ΔEx16, and enhances DNA synthesis mainly through the PI3K-AKT pathway in an adherent culture. We showed here that only the combination of nectin-4 and p95-ErbB2, but not that of nectin-4 and ErbB2 or that of nectin-4 and ErbB2ΔEx16, cooperatively enhanced multilayered T47D cell proliferation through the Hippo pathway-mediated SOX2 gene expression in an adherent culture. T47D cells expressed the components of the apical junctional complex (AJC) consisting of adherens junctions (AJs) and tight junctions and cell polarity molecules, but not the AJ component afadin. The AJC and apicobasal polarity were disorganized in T47D cells in a monolayer and T47D cells stably expressing both nectin-4 and p95-ErbB2 in multilayers. These results indicate that nectin-4 and p95-ErbB2 play a stimulatory role in multilayered proliferation in an adherent culture.
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Affiliation(s)
- Shin Kedashiro
- From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Takeshi Kameyama
- From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Kiyohito Mizutani
- From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Yoshimi Takai
- From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
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12
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Wynn CS, Tang SC. Anti-HER2 therapy in metastatic breast cancer: many choices and future directions. Cancer Metastasis Rev 2022; 41:193-209. [PMID: 35142964 PMCID: PMC8924093 DOI: 10.1007/s10555-022-10021-x] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 01/19/2022] [Indexed: 12/30/2022]
Abstract
Metastatic HER2 + breast cancer is an expanding area of drug development and research, with three new drugs approved in 2020 alone. While first-line therapy is well-established for metastatic HER2 + breast cancer, the standard of care for second-line therapy will likely be changing soon based on the results of the DESTINY-Breast03 trial. In the third-line setting, many options are available. Considerations in choosing between regimens in the third-line include resistance to trastuzumab, the presence of brain metastases, and tolerability. High rates of resistance exist in this setting particularly due to expression of p95, a truncated form of HER2 that constitutively activates downstream signaling pathways. We suggest a tyrosine kinase inhibitor (TKI)-based regimen because of the activity of TKIs in brain metastases and in p95-expressing tumors. Attempts to overcome resistance to anti-HER2 therapies with PI3K inhibitors, mTOR inhibitors, and CDK 4/6 inhibitors are an active area of research. In the future, biomarkers are needed to help predict which therapies patients may benefit from the most. We review the many new drugs in development, including those with novel mechanisms of action.
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Affiliation(s)
- Carrie S Wynn
- Cancer Center and Research Institute, University of Mississippi Medical Center, Guyton Research Building, G-651-07, 2500 North State Street, Jackson, MS, 39216, USA
| | - Shou-Ching Tang
- Cancer Center and Research Institute, University of Mississippi Medical Center, Guyton Research Building, G-651-07, 2500 North State Street, Jackson, MS, 39216, USA.
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13
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Wakefield DL, Tobin SJ, Schmolze D, Jovanovic-Talisman T. Molecular Imaging of HER2 in Patient Tissues with Touch Prep-Quantitative Single Molecule Localization Microscopy. Methods Mol Biol 2022; 2394:231-248. [PMID: 35094332 PMCID: PMC9121336 DOI: 10.1007/978-1-0716-1811-0_15] [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] [Indexed: 01/03/2023]
Abstract
Biomolecules can be investigated at the nanoscale with quantitative single molecule localization microscopy (qSMLM). This technique, which achieves single molecule sensitivity, can probe how membrane receptors are organized under both normal and pathological conditions. While a number of receptors have been extensively studied in cultured cells, technical challenges have largely impeded their robust quantification in tissue samples. To rigorously interrogate tissue samples, methodological advancements are needed in three areas: analytical preparation of the sample, proper characterization of fluorescent reporters, and rapid/unbiased data analysis. Towards these ends, we have combined qSMLM with a touch preparation technique (touch prep-qSMLM). In this new method, touch prep is first used to obtain monolayers of patient cells. Then, highly selective, fluorescently labeled probes are used to detect the receptors of interest on the plasma membranes of cells. Finally, quantitative algorithms are used to analyze the imaging data. Using this touch prep-qSMLM methodology, we interrogated the density and nano-organization of human epidermal growth factor receptor 2 (HER2) in fresh breast cancer tissues. Touch prep-qSMLM agreed well with current clinical methods. Importantly, touch prep-qSMLM can be easily extended to other pathological conditions and ultimately used in precision medicine.
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Affiliation(s)
- Devin L Wakefield
- Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
- Amgen, South San Francisco, CA, USA
| | - Steven J Tobin
- Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Daniel Schmolze
- Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Tijana Jovanovic-Talisman
- Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
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14
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Faure C, Djerbi-Bouillié R, Domingot A, Bouzinba-Segard H, Taouji S, Saidi Y, Bernard S, Carallis F, Rothe-Walther R, Lenormand JL, Chevet E, Bourdoulous S. Allosteric Inhibition of HER2 by Moesin-Mimicking Compounds Targets HER2-Positive Cancers and Brain Metastases. Cancer Res 2021; 81:5464-5476. [PMID: 34493594 DOI: 10.1158/0008-5472.can-21-0162] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 07/27/2021] [Accepted: 09/02/2021] [Indexed: 11/16/2022]
Abstract
Therapies targeting the tyrosine kinase receptor HER2 have significantly improved survival of patients with HER2+ cancer. However, both de novo and acquired resistance remain a challenge, particularly in the brain metastatic setting. Here we report that, unlike other HER tyrosine kinase receptors, HER2 possesses a binding motif in its cytosolic juxtamembrane region that allows interaction with members of the Ezrin/Radixin/Moesin (ERM) family. Under physiologic conditions, this interaction controls the localization of HER2 in ERM-enriched domains and stabilizes HER2 in a catalytically repressed state. In HER2+ breast cancers, low expression of Moesin correlated with increased HER2 expression. Restoring expression of ERM proteins in HER2+ breast cancer cells was sufficient to revert HER2 activation and inhibit HER2-dependent proliferation. A high-throughput assay recapitulating the HER2-ERM interaction allowed for screening of about 1,500 approved drugs. From this screen, we found Zuclopenthixol, an antipsychotic drug that behaved as a Moesin-mimicking compound, because it directly binds the juxtamembrane region of HER2 and specifically inhibits HER2 activation in HER2+ cancers, as well as activation of oncogenic mutated and truncated forms of HER2. Zuclopenthixol efficiently inhibited HER2+ breast tumor progression in vitro and in vivo and, more importantly, showed significant activity on HER2+ brain tumor progression. Collectively, these data reveal a novel class of allosteric HER2 inhibitors, increasing the number of approaches to consider for intervention on HER2+ breast cancers and brain metastases. SIGNIFICANCE: This study demonstrates the functional role of Moesin in maintaining HER2 in a catalytically repressed state and provides novel therapeutic approaches targeting HER2+ breast cancers and brain metastasis using Moesin-mimicking compounds.
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Affiliation(s)
- Camille Faure
- Université de Paris, Institut Cochin, Inserm, CNRS, Paris, France.
| | | | - Anaïs Domingot
- Université de Paris, Institut Cochin, Inserm, CNRS, Paris, France
| | | | - Saïd Taouji
- Inserm, Université de Bordeaux, Institut Bergonié, Bordeaux, France
| | - Yanis Saidi
- Université de Paris, Institut Cochin, Inserm, CNRS, Paris, France
| | - Sandra Bernard
- Université de Paris, Institut Cochin, Inserm, CNRS, Paris, France
| | | | - Romy Rothe-Walther
- TIMC-IMAG Laboratory, CNRS, Université Joseph Fourier, UFR de Médecine, La Tronche, France
| | - Jean-Luc Lenormand
- TIMC-IMAG Laboratory, CNRS, Université Joseph Fourier, UFR de Médecine, La Tronche, France
| | - Eric Chevet
- Inserm, Université de Bordeaux, Institut Bergonié, Bordeaux, France
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15
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Pupa SM, Ligorio F, Cancila V, Franceschini A, Tripodo C, Vernieri C, Castagnoli L. HER2 Signaling and Breast Cancer Stem Cells: The Bridge behind HER2-Positive Breast Cancer Aggressiveness and Therapy Refractoriness. Cancers (Basel) 2021; 13:cancers13194778. [PMID: 34638263 PMCID: PMC8507865 DOI: 10.3390/cancers13194778] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 09/15/2021] [Accepted: 09/20/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Breast cancer (BC) is not a single disease, but a group of different tumors, and altered HER2 expression defines a particularly aggressive subtype. Although HER2 pharmacological inhibition has dramatically improved the prognosis of HER2-positive BC patients, there is still an urgent need for improved knowledge of HER2 biology and mechanisms underlying HER2-driven aggressiveness and drug susceptibility. Emerging data suggest that the clinical efficacy of molecularly targeted therapies is related to their ability to target breast cancer stem cells (BCSCs), a population that is not only self-sustaining and able to differentiate into distinct lineages, but also contributes to tumor growth, aggressiveness, metastasis and treatment resistance. The aim of this review is to provide an overview of how the full-length HER2 receptor, the d16HER2 splice variant and the truncated p95HER2 variants are involved in the regulation and maintenance of BCSCs. Abstract HER2 overexpression/amplification occurs in 15–20% of breast cancers (BCs) and identifies a highly aggressive BC subtype. Recent clinical progress has increased the cure rates of limited-stage HER2-positive BC and significantly prolonged overall survival in patients with advanced disease; however, drug resistance and tumor recurrence remain major concerns. Therefore, there is an urgent need to increase knowledge regarding HER2 biology and implement available treatments. Cancer stem cells (CSCs) represent a subset of malignant cells capable of unlimited self-renewal and differentiation and are mainly considered to contribute to tumor onset, aggressiveness, metastasis, and treatment resistance. Seminal studies have highlighted the key role of altered HER2 signaling in the maintenance/enrichment of breast CSCs (BCSCs) and elucidated its bidirectional communication with stemness-related pathways, such as the Notch and Wingless/β-catenin cascades. d16HER2, a splice variant of full-length HER2 mRNA, has been identified as one of the most oncogenic HER2 isoform significantly implicated in tumorigenesis, epithelial-mesenchymal transition (EMT)/stemness and the response to targeted therapy. In addition, expression of a heterogeneous collection of HER2 truncated carboxy-terminal fragments (CTFs), collectively known as p95HER2, identifies a peculiar subgroup of HER2-positive BC with poor prognosis, with the p95HER2 variants being able to regulate CSC features. This review provides a comprehensive overview of the current evidence regarding HER2-/d16HER2-/p95HER2-positive BCSCs in the context of the signaling pathways governing their properties and describes the future prospects for targeting these components to achieve long-lasting tumor control.
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Affiliation(s)
- Serenella M. Pupa
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, AmadeoLab, Via Amadeo 42, 20133 Milan, Italy; (A.F.); (L.C.)
- Correspondence: ; Tel.: +39-022-390-2573; Fax: +39-022-390-2692
| | - Francesca Ligorio
- Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy; (F.L.); or (C.V.)
| | - Valeria Cancila
- Tumor Immunology Unit, University of Palermo, Corso Tukory 211, 90134 Palermo, Italy; (V.C.); (C.T.)
| | - Alma Franceschini
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, AmadeoLab, Via Amadeo 42, 20133 Milan, Italy; (A.F.); (L.C.)
| | - Claudio Tripodo
- Tumor Immunology Unit, University of Palermo, Corso Tukory 211, 90134 Palermo, Italy; (V.C.); (C.T.)
| | - Claudio Vernieri
- Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy; (F.L.); or (C.V.)
- IFOM the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
| | - Lorenzo Castagnoli
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, AmadeoLab, Via Amadeo 42, 20133 Milan, Italy; (A.F.); (L.C.)
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16
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Li YQ, Zheng Z, Liu QX, Lu X, Zhou D, Zhang J, Zheng H, Dai JG. Repositioning of Antiparasitic Drugs for Tumor Treatment. Front Oncol 2021; 11:670804. [PMID: 33996598 PMCID: PMC8117216 DOI: 10.3389/fonc.2021.670804] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 04/13/2021] [Indexed: 12/24/2022] Open
Abstract
Drug repositioning is a strategy for identifying new antitumor drugs; this strategy allows existing and approved clinical drugs to be innovatively repurposed to treat tumors. Based on the similarities between parasitic diseases and cancer, recent studies aimed to investigate the efficacy of existing antiparasitic drugs in cancer. In this review, we selected two antihelminthic drugs (macrolides and benzimidazoles) and two antiprotozoal drugs (artemisinin and its derivatives, and quinolines) and summarized the research progresses made to date on the role of these drugs in cancer. Overall, these drugs regulate tumor growth via multiple targets, pathways, and modes of action. These antiparasitic drugs are good candidates for comprehensive, in-depth analyses of tumor occurrence and development. In-depth studies may improve the current tumor diagnoses and treatment regimens. However, for clinical application, current investigations are still insufficient, warranting more comprehensive analyses.
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Affiliation(s)
| | | | | | | | | | | | - Hong Zheng
- Department of Thoracic Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Ji-Gang Dai
- Department of Thoracic Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
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17
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Kedashiro S, Kameyama T, Mizutani K, Takai Y. Nectin-4 and p95-ErbB2 cooperatively regulate Hippo signaling-dependent SOX2 gene expression, enhancing anchorage-independent T47D cell proliferation. Sci Rep 2021; 11:7344. [PMID: 33795719 PMCID: PMC8016986 DOI: 10.1038/s41598-021-86437-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/10/2021] [Indexed: 12/17/2022] Open
Abstract
Nectin-4, upregulated in various cancer cells, cis-interacts with ErbB2 and its trastuzumab-resistant splice variants, p95-ErbB2 and ErbB2∆Ex16, enhancing DNA synthesis through the PI3K-AKT signaling in human breast cancer T47D cells in an adherent culture. We found here that nectin-4 and p95-ErbB2, but not nectin-4 and either ErbB2 or ErbB2∆Ex16, cooperatively enhanced SOX2 gene expression and cell proliferation in a suspension culture. This enhancement of T47D cell proliferation in a suspension culture by nectin-4 and p95-ErbB2 was dependent on the SOX2 gene expression. In T47D cells, nectin-4 and any one of p95-ErbB2, ErbB2, or ErbB2∆Ex16 cooperatively activated the PI3K-AKT signaling, known to induce the SOX2 gene expression, to similar extents. However, only a combination of nectin-4 and p95-ErbB2, but not that of nectin-4 and either ErbB2 or ErbB2∆Ex16, cooperatively enhanced the SOX2 gene expression. Detailed studies revealed that only nectin-4 and p95-ErbB2 cooperatively activated the Hippo signaling. YAP inhibited the SOX2 gene expression in this cell line and thus the MST1/2-LATS1/2 signaling-mediated YAP inactivation increased the SOX2 gene expression. These results indicate that only the combination of nectin-4 and p95-ErbB2, but not that of nectin-4 and either ErbB2 or ErbB2∆Ex16, cooperatively regulates the Hippo signaling-dependent SOX2 gene expression, enhancing anchorage-independent T47D cell proliferation.
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Affiliation(s)
- Shin Kedashiro
- Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan
| | - Takeshi Kameyama
- Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan
| | - Kiyohito Mizutani
- Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
| | - Yoshimi Takai
- Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
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18
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Frankhauser DE, Jovanovic‐Talisman T, Lai L, Yee LD, Wang LV, Mahabal A, Geradts J, Rockne RC, Tomsic J, Jones V, Sistrunk C, Miranda‐Carboni G, Dietze EC, Erhunmwunsee L, Hyslop T, Seewaldt VL. Spatiotemporal strategies to identify aggressive biology in precancerous breast biopsies. WIREs Mech Dis 2021; 13:e1506. [PMID: 33001587 PMCID: PMC8544796 DOI: 10.1002/wsbm.1506] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 08/21/2020] [Accepted: 08/24/2020] [Indexed: 01/12/2023]
Abstract
Over 90% of breast cancer is cured; yet there remain highly aggressive breast cancers that develop rapidly and are extremely difficult to treat, much less prevent. Breast cancers that rapidly develop between breast image screening are called "interval cancers." The efforts of our team focus on identifying multiscale integrated strategies to identify biologically aggressive precancerous breast lesions. Our goal is to identify spatiotemporal changes that occur prior to development of interval breast cancers. To accomplish this requires integration of new technology. Our team has the ability to perform single cell in situ transcriptional profiling, noncontrast biological imaging, mathematical analysis, and nanoscale evaluation of receptor organization and signaling. These technological innovations allow us to start to identify multidimensional spatial and temporal relationships that drive the transition from biologically aggressive precancer to biologically aggressive interval breast cancer. This article is categorized under: Cancer > Computational Models Cancer > Molecular and Cellular Physiology Cancer > Genetics/Genomics/Epigenetics.
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Affiliation(s)
- David E. Frankhauser
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | | | - Lily Lai
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Lisa D. Yee
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Lihong V. Wang
- Department of Medical EngineeringCalifornia Institute of TechnologyPasadena, CaliforniaUSA
| | - Ashish Mahabal
- Center for Data Driven DiscoveryCalifornia Institute of TechnologyPasadena, CaliforniaUSA
| | - Joseph Geradts
- Department of PathologyDuke UniversityDurhamNorth CarolinaUSA
| | - Russell C. Rockne
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Jerneja Tomsic
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Veronica Jones
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Christopher Sistrunk
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | | | - Eric C. Dietze
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Loretta Erhunmwunsee
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Terry Hyslop
- Department of BiostatisticsDuke UniversityDurhamNorth CarolinaUSA
| | - Victoria L. Seewaldt
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
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19
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Primary Trastuzumab Resistance After (Neo)adjuvant Trastuzumab-containing Treatment for Patients With HER2-positive Breast Cancer in Real-world Practice. Clin Breast Cancer 2021; 21:191-198. [PMID: 33549471 DOI: 10.1016/j.clbc.2020.09.003] [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: 02/21/2020] [Revised: 09/01/2020] [Accepted: 09/03/2020] [Indexed: 11/20/2022]
Abstract
BACKGROUND It is difficult to define patients with primary trastuzumab resistance (PTR) after (neo)adjuvant trastuzumab with minimal data and understanding of the actual prevalence, prognosis, and potential treatment strategies in the real-world setting. PATIENTS AND METHODS The medical records of 1096 patients with human epidermal growth factor receptor 2-positive early-stage breast cancer who had received (neo)adjuvant trastuzumab-containing treatment from 2010 to 2016 in the Cancer Hospital and Chinese Academy of Medical Sciences were reviewed. PTR was defined as recurrence during adjuvant trastuzumab or within 12 months from their last (neo)adjuvant trastuzumab dosage. The cutoff date for data collection was September 1, 2018, with a median follow-up time of 46 months. RESULTS A total of 126 recurrences were observed, and 75 (6.8%; 75/1096) of them were categorized as PTR; the remaining were non-PTR. The prognosis of patients in the PTR group was much inferior to those in the non-PTR group (27 months vs. not reached; P < .01). As expected, patients with PTR did possess a much lower response rate to first-line trastuzumab-containing therapy (27.3% vs. 61.9%; P = .02). Subgroup analyses indicated that patients in the PTR group seemed to get little survival benefit from the reuse of trastuzumab compared with those without trastuzumab (26 months vs. 28 months; P = .80). However, in the non-PTR group, re-treatment with trastuzumab in the metastatic setting prolonged the survival of patients compared to those without trastuzumab (not reached vs. 34 months; P = .04). CONCLUSION This study verified the rationality of present definition of PTR after (neo)adjuvant trastuzumab. Patients with PTR did have a poor prognosis. Further research and clinical trials are required to establish the best treatment patterns for these patients.
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20
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Klocker EV, Suppan C. Biomarkers in Her2- Positive Disease. Breast Care (Basel) 2020; 15:586-593. [PMID: 33447232 DOI: 10.1159/000512283] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 10/14/2020] [Indexed: 12/11/2022] Open
Abstract
Background Breast cancer is a heterogeneous disease with well-known characteristics such as hormone receptor (HR) status and human epidermal growth factor (Her)2 status. Although Her2 represents an established treatment target, the development of resistance mechanisms during treatment, cardiotoxicity, and a worse response to standard therapies lead to worse outcomes. Summary Therefore, we investigated various biomarkers in breast cancer such as Her2 mutations, Her2 heterogeneity, HR, PIK3CA, PTEN, programmed death receptor ligand 1 (PD-L1), tumor-infiltrating lymphocytes (TIL), micro RNA (miRNA), and BRCA mutations with regard to their clinical impact in Her2-positive disease. HR status and Her2 status, such as the presence of PIK3CA mutations, already play a role in treatment decision-making processes, whereas other biomarkers like PD-L1 status or TIL represent promising future markers. The influence of BRCA mutations in Her2-positive disease, Her2 mutations, and the impact of miRNA is vague to date. Antibody-drug conjugates (ADC) such as T-DM have been established as important treatment strategies, especially in Her2-positive disease. Key Message However, up-to-date biomarkers appropriate for clinical practice are missing. Further studies are needed.
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Affiliation(s)
| | - Christoph Suppan
- Department of Oncology, Medical University of Graz, Graz, Austria
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21
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Nishie M, Suzuki E, Hattori M, Kawaguch K, Kataoka TR, Hirata M, Pu F, Kotake T, Tsuda M, Yamaguchi A, Sugie T, Toi M. Downregulated ATP6V1B1 expression acidifies the intracellular environment of cancer cells leading to resistance to antibody-dependent cellular cytotoxicity. Cancer Immunol Immunother 2020; 70:817-830. [PMID: 33000417 DOI: 10.1007/s00262-020-02732-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 09/20/2020] [Indexed: 11/30/2022]
Abstract
Among several mechanisms for the resistance of human epidermal growth factor receptor 2-overexpressing (HER2 +) cancer cells to trastuzumab, little is known regarding the mechanism underlying the resistance to trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Cell death due to ADCC is caused by apoptosis of target cells induced by granzymes released from natural killer cells. Because optimal granzyme physiological activity occurs at neutral pH, we assumed that the pH of the intracellular environment influences the cytotoxic effects of granzymes. We established ADCC-resistant cells and compared them with wild-type cells in terms of the expression of intracellular pH-regulating genes. The expression of ATP6V1B1, which encodes a component of vacuolar ATPases, was downregulated in the ADCC-resistant cells. Thus, to functionally characterize ATP6V1B1, we used a CRISPR/Cas9 system to generate ATP6V1B1-knockout SKBR3 and JIMT-1 cells (both HER2 + human breast cancer cell line). The resulting cells exhibited significantly less ADCC than the control SKBR3 and JIMT-1 cells. The intracellular pH of the ATP6V1B1-knockout SKBR3 and JIMT-1 cells was significantly lower than control SKBR3 and JIMT-1cells. An analysis of granzyme dynamics during the ADCC reaction in cancer cells revealed that granzymes degraded intracellularly in the control SKBR3 and JIMT-1 cells and accumulated in ATP6V1B1-knockout cells, but were not cytotoxic. These findings suggest that decreased vacuolar ATPase activity alters the cytoplasmic pH of cancer cells to create an environment that is less suitable for granzyme bioactivity, which adversely affects the induction of apoptosis of cancer cells by NK cells.
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Affiliation(s)
- Mariko Nishie
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Eiji Suzuki
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan. .,Department of Breast Surgery, Kyoto University Hospital, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.
| | - Masakazu Hattori
- Department of Immunosenescence, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kosuke Kawaguch
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tatsuki R Kataoka
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Masahiro Hirata
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Fengling Pu
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takeshi Kotake
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Moe Tsuda
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ayane Yamaguchi
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomoharu Sugie
- Department of Breast Surgery, Kansai Medical University, Osaka, Japan
| | - Masakazu Toi
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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22
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Kedashiro S, Sugiura A, Mizutani K, Takai Y. Nectin-4 cis-interacts with ErbB2 and its trastuzumab-resistant splice variants, enhancing their activation and DNA synthesis. Sci Rep 2019; 9:18997. [PMID: 31831814 PMCID: PMC6908695 DOI: 10.1038/s41598-019-55460-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 11/26/2019] [Indexed: 12/31/2022] Open
Abstract
Nectin-4 cell adhesion molecule and ErbB2 tyrosine kinase receptor are upregulated in many cancers, including breast cancer, and promote cancer cell proliferation and metastasis. Using human breast cancer cell lines T47D and SUM190-PT, in which both nectin-4 and ErbB2 were upregulated, we showed here that nectin-4 cis-interacted with ErB2 and enhanced its dimerization and activation, followed by the activation of the phosphoinositide 3-kinase-AKT signalling pathway for DNA synthesis. The third immunoglobulin-like domain of nectin-4 cis-interacted with domain IV of ErbB2. This region differs from the trastuzumab-interacting region but is included in the trastuzumab-resistant splice variants of ErbB2, p95-ErbB2 and ErbB2ΔEx16. Nectin-4 also cis-interacted with these trastuzumab-resistant splice variants and enhanced the activation of the phosphoinositide 3-kinase-AKT signalling pathway for DNA synthesis. In addition, nectin-4 enhanced the activation of the p95-ErbB2-induced JAK-STAT3 signalling pathway, but not the ErbB2- or ErbB2ΔEx16-induced JAK-STAT3 signalling pathway. These results indicate that nectin-4 cis-interacts with ErbB2 and its trastuzumab-resistant splice variants and enhances the activation of these receptors and downstream signalling pathways in a novel mechanism.
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Affiliation(s)
- Shin Kedashiro
- From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan
| | - Ayumu Sugiura
- From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan
| | - Kiyohito Mizutani
- From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
| | - Yoshimi Takai
- From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
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Kim SB, Do IG, Tsang J, Kim TY, Yap YS, Cornelio G, Gong G, Paik S, Lee S, Ng TY, Park S, Oh HS, Chiu J, Sohn J, Lee M, Choi YJ, Lee EM, Park KH, Nathaniel C, Ro J. BioPATH: A Biomarker Study in Asian Patients with HER2+ Advanced Breast Cancer Treated with Lapatinib and Other Anti-HER2 Therapy. Cancer Res Treat 2019; 51:1527-1539. [PMID: 31163957 PMCID: PMC6790855 DOI: 10.4143/crt.2018.598] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Accepted: 03/19/2019] [Indexed: 12/19/2022] Open
Abstract
PURPOSE BioPATH is a non-interventional study evaluating the relationship of molecular biomarkers (PTEN deletion/downregulation, PIK3CA mutation, truncated HER2 receptor [p95HER2], and tumor HER2 mRNA levels) to treatment responses in Asian patients with HER2+ advanced breast cancer treated with lapatinib and other HER2-targeted agents. Materials and Methods Female Asian HER2+ breast cancer patients (n=154) who were candidates for lapatinib-based treatment following metastasis and having an available primary tumor biopsy specimen were included. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, overall survival on lapatinib, correlation between biomarker status and PFS for any previous trastuzumab-based treatment, and conversion/conservation rates of the biomarker status between tissue samples collected at primary diagnosis and at recurrence/metastasis. Potential relationships between tumor mRNA levels of HER2 and response to lapatinib-based therapy were also explored. RESULTS p95HER2, PTEN deletion/downregulation, and PIK3CA mutation did not demonstrate any significant co-occurrence pattern and were not predictive of clinical outcomes on either lapatinib-based treatment or any previous trastuzumab-based therapy in the metastatic setting. Proportions of tumors positive for p95HER2 expression, PIK3CA mutation, and PTEN deletion/down-regulation at primary diagnosis were 32%, 31.2%, and 56.2%, respectively. Despite limited availability of paired samples, biomarker status patterns were conserved in most samples. HER2 mRNA levels were not predictive of PFS on lapatinib. CONCLUSION The prevalence of p95HER2 expression, PIK3CA mutation, and PTEN deletion/downregulation at primary diagnosis were similar to previous reports. Importantly, no difference was observed in clinical outcome based on the status of these biomarkers, consistent with reports from other studies.
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Affiliation(s)
- Sung-Bae Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - In-Gu Do
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Janice Tsang
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Tae-You Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Yoon-Sim Yap
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore
| | - Gerardo Cornelio
- Department of Medicine, San Juan De Dios Hospital, Manila, Philippines
| | - Gyungyub Gong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Soonmyung Paik
- Department of Medical Oncology and Severance Biomedical Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Suee Lee
- Department of Internal Medicine, Dong-A University Hospital, Busan, Korea
| | - Ting-Ying Ng
- Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong, China
| | - Sarah Park
- The Center for Anti-Cancer Companion Diagnostics, Bio-MAX/ N-Bio, Seoul National University, Seoul, Korea
| | - Ho-Suk Oh
- Department of Hematology- Oncology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea
| | - Joanne Chiu
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Joohyuk Sohn
- Division of Medical Oncology, Yonsei Cancer Center, Seoul, Korea
| | - Moonhee Lee
- Division of Hematology-Oncology, Inha University Hospital, Incheon, Korea
| | - Young-Jin Choi
- Department of Hematology- Oncology, Pusan National University Hospital, Busan, Korea
| | - Eun Mi Lee
- Department of Internal Medicine, Kosin University Gospel Hospital, Busan, Korea
| | - Kyong-Hwa Park
- Department of Internal Medicine, Korea University Anam Hospital, Seoul, Korea
| | | | - Jungsil Ro
- Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea
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25
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Brix DM, Tvingsholm SA, Hansen MB, Clemmensen KB, Ohman T, Siino V, Lambrughi M, Hansen K, Puustinen P, Gromova I, James P, Papaleo E, Varjosalo M, Moreira J, Jäättelä M, Kallunki T. Release of transcriptional repression via ErbB2-induced, SUMO-directed phosphorylation of myeloid zinc finger-1 serine 27 activates lysosome redistribution and invasion. Oncogene 2019; 38:3170-3184. [PMID: 30622337 DOI: 10.1038/s41388-018-0653-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 11/21/2018] [Accepted: 12/11/2018] [Indexed: 01/08/2023]
Abstract
HER2/ErbB2 activation turns on transcriptional processes that induce local invasion and lead to systemic metastasis. The early transcriptional changes needed for ErbB2-induced invasion are poorly understood. Here, we link ErbB2 activation to invasion via ErbB2-induced, SUMO-directed phosphorylation of a single serine residue, S27, of the transcription factor myeloid zinc finger-1 (MZF1). Utilizing an antibody against MZF1-pS27, we show that the phosphorylation of S27 correlates significantly (p < 0.0001) with high-level expression of ErbB2 in primary invasive breast tumors. Phosphorylation of MZF1-S27 is an early response to ErbB2 activation and results in increased transcriptional activity of MZF1. It is needed for the ErbB2-induced expression of MZF1 target genes CTSB and PRKCA, and invasion of single-cells from ErbB2-expressing breast cancer spheroids. The phosphorylation of MZF1-S27 is preceded by poly-SUMOylation of K23, which can make S27 accessible to efficient phosphorylation by PAK4. Based on our results, we suggest for an activation mechanism where phosphorylation of MZF1-S27 triggers MZF1 dissociation from its transcriptional repressors such as the CCCTC-binding factor (CTCF). Our findings increase understanding of the regulation of invasive signaling in breast cancer by uncovering a detailed biological mechanism of how ErbB2 activation can rapidly lead to its invasion-promoting target gene expression and invasion.
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Affiliation(s)
- Ditte Marie Brix
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Siri Amanda Tvingsholm
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Malene Bredahl Hansen
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Knut Bundgaard Clemmensen
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Tiina Ohman
- Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, 00014UH, Helsinki, Finland
| | - Valentina Siino
- Institute for Immunotechnology, Medicon Village, Lund University, 223 81, Lund, Sweden
| | - Matteo Lambrughi
- Computational Biology Laboratory, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, 2100, Copenhagen, Denmark
| | - Klaus Hansen
- Biotech Research and Innovation Center, Copenhagen University, 2200, Copenhagen, Denmark
| | - Pietri Puustinen
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Irina Gromova
- Breast Cancer Biology, Unit of Genome Integrity, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, 2100, Copenhagen, Denmark
| | - Peter James
- Turku Centre for Biotechnology, Åbo Akademi University and University of Turku, 20014, Turku, Finland
| | - Elena Papaleo
- Computational Biology Laboratory, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, 2100, Copenhagen, Denmark
| | - Markku Varjosalo
- Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, 00014UH, Helsinki, Finland
| | - José Moreira
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark
| | - Marja Jäättelä
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark.
| | - Tuula Kallunki
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark. .,Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
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26
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Tobin SJ, Wakefield DL, Jones V, Liu X, Schmolze D, Jovanović-Talisman T. Single molecule localization microscopy coupled with touch preparation for the quantification of trastuzumab-bound HER2. Sci Rep 2018; 8:15154. [PMID: 30310083 PMCID: PMC6181918 DOI: 10.1038/s41598-018-33225-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 09/25/2018] [Indexed: 12/11/2022] Open
Abstract
All breast cancers are assessed for levels of human epidermal growth factor receptor 2 (HER2). Fluorescence in situ hybridization (FISH) and immunohistochemistry are currently used to determine if a patient is eligible for anti-HER2 therapy. Limitations of both tests include variability and relatively long processing times. Additionally, neither test determines whether HER2 contains the extracellular domain. While truncated in some tumors, this domain is required for binding of the therapeutic antibody trastuzumab. Here, trastuzumab was used to directly detect HER2 with quantitative single molecule localization microscopy (qSMLM). In proof of concept studies, our new method rapidly quantified both HER2 density and features of nano-organization. In cultured cells, the method was sensitive to subtle variations in HER2 expression. To assess patient samples, we combined qSMLM with tissue touch preparation (touch prep-qSMLM) and examined large areas of intact membranes. For cell lines and patient samples, HER2 copy numbers from FISH showed a significant positive correlation with detected densities from qSMLM and trended with HER2 cluster occupancy.
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Affiliation(s)
- Steven J Tobin
- Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA
| | - Devin L Wakefield
- Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA
| | - Veronica Jones
- Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA
| | - Xueli Liu
- Division of Biostatistics, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA
| | - Daniel Schmolze
- Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA
| | - Tijana Jovanović-Talisman
- Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA.
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27
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Sperinde J, Huang W, Vehtari A, Chenna A, Kellokumpu-Lehtinen PL, Winslow J, Bono P, Lie YS, Petropoulos CJ, Weidler J, Joensuu H. p95HER2 Methionine 611 Carboxy-Terminal Fragment Is Predictive of Trastuzumab Adjuvant Treatment Benefit in the FinHer Trial. Clin Cancer Res 2018. [PMID: 29535130 DOI: 10.1158/1078-0432.ccr-17-3250] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Purpose: Expression of p95HER2 (p95), a truncated form of the HER2 receptor, which lacks the trastuzumab binding site but retains kinase activity, has been reported as a prognostic biomarker for poor outcomes in patients with trastuzumab-treated HER2-positive metastatic breast cancer. The impact of p95 expression on trastuzumab treatment efficacy in early HER2-positive breast cancer is less clear. In the current study, p95 was tested as a predictive marker of trastuzumab treatment benefit in the HER2-positive subset of the FinHer adjuvant phase III trial.Experimental Design: In the FinHer trial, 232 patients with HER2-positive early breast cancer were randomized to receive chemotherapy plus 9 weeks of trastuzumab or no trastuzumab treatment. Quantitative p95 protein expression was measured in formalin-fixed paraffin-embedded samples using the p95 VeraTag assay (Monogram Biosciences), specific for the M611 form of p95. Quantitative HER2 protein expression was measured using the HERmark assay (Monogram Biosciences). Distant disease-free survival (DDFS) was used as the primary outcome measure.Results: In the arm receiving chemotherapy only, increasing log10(p95) correlated with shorter DDFS (HR, 2.0; P = 0.02). In the arm receiving chemotherapy plus trastuzumab (N = 95), increasing log10(p95) was not correlated with a shorter DDFS. In a combined analysis of both treatment arms, high breast tumor p95 content was significantly correlated with trastuzumab treatment benefit in multivariate models (interaction P = 0.01).Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 24(13); 3046-52. ©2018 AACR.
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Affiliation(s)
- Jeff Sperinde
- Monogram Biosciences, Inc., Laboratory Corporation of America Holdings, South San Francisco, California.
| | - Weidong Huang
- Monogram Biosciences, Inc., Laboratory Corporation of America Holdings, South San Francisco, California
| | - Aki Vehtari
- Helsinki Institute for Information Technology HIIT, Department of Computer Science, Aalto University, Finland
| | - Ahmed Chenna
- Monogram Biosciences, Inc., Laboratory Corporation of America Holdings, South San Francisco, California
| | | | - John Winslow
- Monogram Biosciences, Inc., Laboratory Corporation of America Holdings, South San Francisco, California
| | - Petri Bono
- Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Yolanda S Lie
- Monogram Biosciences, Inc., Laboratory Corporation of America Holdings, South San Francisco, California
| | - Christos J Petropoulos
- Monogram Biosciences, Inc., Laboratory Corporation of America Holdings, South San Francisco, California
| | - Jodi Weidler
- Monogram Biosciences, currently Cepheid, Sunnyvale, California
| | - Heikki Joensuu
- Department of Oncology, Helsinki University Hospital & Helsinki University, Helsinki, Finland
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28
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Gu S, Ngamcherdtrakul W, Reda M, Hu Z, Gray JW, Yantasee W. Lack of acquired resistance in HER2-positive breast cancer cells after long-term HER2 siRNA nanoparticle treatment. PLoS One 2018; 13:e0198141. [PMID: 29879129 PMCID: PMC5991725 DOI: 10.1371/journal.pone.0198141] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 05/14/2018] [Indexed: 01/09/2023] Open
Abstract
Intrinsic and acquired resistance to current HER2 targeted therapies remains a challenge in clinics. We have developed a therapeutic HER2 siRNA delivered using mesoporous silica nanoparticles modified with polymers and conjugated with HER2 targeting antibodies. Our previous studies have shown that our HER2 siRNA nanoparticles could overcome intrinsic and acquired resistance to trastuzumab and lapatinib in HER2-positive breast cancers. In this study, we investigated the effect of long-term (7 months) treatment using our therapeutic HER2 siRNA. Even after the removal of HER2 siRNA, the long-term treated cells grew much slower (67% increase in doubling time) than cells that have not received any treatment. The treated cells did not undergo epithelial-mesenchymal transition or showed enrichment of tumor initiating cells. Unlike trastuzumab and lapatinib, which induced resistance in BT474 cells after 6 months of treatment, HER2 siRNA did not induce resistance to HER2 siRNA, trastuzumab, or lapatinib. HER2 ablation with HER2 siRNA prevented reactivation of HER2 signaling that was observed in cells resistant to lapatinib. Altogether, our results indicate that a HER2 siRNA based therapeutic provides a more durable inhibition of HER2 signaling in vitro and can potentially be more effective than the existing therapeutic monoclonal antibodies and small molecule inhibitors.
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Affiliation(s)
- Shenda Gu
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Worapol Ngamcherdtrakul
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, United States of America
- PDX Pharmaceuticals, LLC, Portland, Oregon, United States of America
| | - Moataz Reda
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Zhi Hu
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Joe W. Gray
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Wassana Yantasee
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, United States of America
- PDX Pharmaceuticals, LLC, Portland, Oregon, United States of America
- * E-mail:
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29
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Expression of truncated HER2 and its prognostic value in HER2-positive breast cancer patients. J Egypt Natl Canc Inst 2018; 30:49-55. [DOI: 10.1016/j.jnci.2018.05.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 05/01/2018] [Accepted: 05/04/2018] [Indexed: 11/18/2022] Open
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30
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Kang CC, Ward TM, Bockhorn J, Schiffman C, Huang H, Pegram MD, Herr AE. Electrophoretic cytopathology resolves ERBB2 forms with single-cell resolution. NPJ Precis Oncol 2018; 2:10. [PMID: 29872719 PMCID: PMC5871910 DOI: 10.1038/s41698-018-0052-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2017] [Revised: 02/10/2018] [Accepted: 02/20/2018] [Indexed: 12/20/2022] Open
Abstract
In addition to canonical oncoproteins, truncated isoforms and proteolysis products are implicated in both drug resistance and disease progression. In HER2-positive breast tumors, expression of truncated HER2 isoforms resulting from alternative translation and/or carboxy-terminal fragments (CTFs) resulting from proteolysis (collectively, t-erbB2) have been associated with shortened progression-free survival of patients. Thus, to advance clinical pathology and inform treatment decisions, we developed a high-selectivity cytopathology assay capable of distinguishing t-erbB2 from full-length HER2 expression without the need for isoform-specific antibodies. Our microfluidic, single-cell western blot, employs electrophoretic separations to resolve full-length HER2 from the smaller t-erbB2 in each ~28 pL single-cell lysate. Subsequently, a pan-HER2 antibody detects all resolved HER2 protein forms via immunoprobing. In analysis of eight breast tumor biopsies, we identified two tumors comprised of 15% and 40% t-erbB2-expressing cells. By single-cell western blotting of the t-erbB2-expressing cells, we observed statistically different ratios of t-erbB2 proteins to full-length HER2 expression. Further, target multiplexing and clustering analyses scrutinized signaling, including ribosomal S6, within the t-erbB2-expressing cell subpopulation. Taken together, cytometric assays that report both protein isoform profiles and signaling state offer cancer classification taxonomies with unique relevance to precisely describing drug resistance mechanisms in which oncoprotein isoforms/fragments are implicated.
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Affiliation(s)
- Chi-Chih Kang
- 1Department of Bioengineering, University of California Berkeley, Berkeley, CA 94720 USA
| | - Toby M Ward
- 2Division of Medical Oncology, Department of Medicine, Stanford University, Stanford, CA 94305 USA
| | - Jessica Bockhorn
- 2Division of Medical Oncology, Department of Medicine, Stanford University, Stanford, CA 94305 USA
| | - Courtney Schiffman
- 3Division of Biostatistics, School of Public Health, University of California Berkeley, Berkeley, CA 94720 USA
| | - Haiyan Huang
- 4Department of Statistics, University of California Berkeley, Berkeley, CA 94720 USA
| | - Mark D Pegram
- 2Division of Medical Oncology, Department of Medicine, Stanford University, Stanford, CA 94305 USA
| | - Amy E Herr
- 1Department of Bioengineering, University of California Berkeley, Berkeley, CA 94720 USA
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Chumsri S, Sperinde J, Liu H, Gligorov J, Spano JP, Antoine M, Moreno Aspitia A, Tan W, Winslow J, Petropoulos CJ, Chenna A, Bates M, Weidler JM, Huang W, Dueck A, Perez EA. High p95HER2/HER2 Ratio Associated With Poor Outcome in Trastuzumab-Treated HER2-Positive Metastatic Breast Cancer NCCTG N0337 and NCCTG 98-32-52 (Alliance). Clin Cancer Res 2018. [PMID: 29530935 DOI: 10.1158/1078-0432.ccr-17-1864] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Purpose: p95HER2 is a truncated form of HER2 that confers resistance to trastuzumab in vitro, but clinical results have been conflicting to date. Given that p95HER2 levels correlate with total HER2 expression levels, which confer better outcomes, we sought to evaluate the p95HER2/HER2 ratio in the North Central Cancer Treatment Group N0337 and N98-32-52 trials.Experimental Design: The HERmark assay and VeraTag technology (Monogram Biosciences) were used to measure total HER2 and p95HER2 expression levels in 91 patient samples.Results: In the multivariate model, increasing total HER2 level was significantly associated with longer (OS; HR, 0.33; P = 0.002) and decreasing p95HER2 level was significantly associated with longer OS (HR, 4.2; P = 0.01). Total HER2 expression level was significantly associated with longer progression-free survival (PFS) (HR, 0.57; P = 0.04), whereas p95HER2 level was not (HR, 1.7; P = 0.25). However, there was a positive association between p95HER2 and total HER2 expression levels (R2 = 0.48; P < 0.001). Consistent with our hypothesis, the ratio of p95HER2/HER2 was significantly associated with worsening PFS (HR, 1.7; P = 0.04) and OS (HR, 2.8; P = 0.002). Patients with the highest tertile of p95HER2/HER2 values had significantly less favorable PFS (HR, 1.8; P = 0.06) and OS (HR, 2.3; P = 0.02).Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 24(13); 3053-8. ©2018 AACR.
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Affiliation(s)
- Saranya Chumsri
- Center for Breast Health, Mayo Clinic, Jacksonville, Florida.
| | - Jeff Sperinde
- Monogram Biosciences, Inc., Laboratory Corporation of America Holdings, South San Francisco, California
| | - Heshan Liu
- Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota
| | | | | | | | | | - Winston Tan
- Center for Breast Health, Mayo Clinic, Jacksonville, Florida
| | - John Winslow
- Monogram Biosciences, Inc., Laboratory Corporation of America Holdings, South San Francisco, California
| | - Christos J Petropoulos
- Monogram Biosciences, Inc., Laboratory Corporation of America Holdings, South San Francisco, California
| | - Ahmed Chenna
- Monogram Biosciences, Inc., Laboratory Corporation of America Holdings, South San Francisco, California
| | | | | | - Weidong Huang
- Monogram Biosciences, Inc., Laboratory Corporation of America Holdings, South San Francisco, California
| | - Amylou Dueck
- Alliance Statistics and Data Center, Mayo Clinic, Scottsdale, Arizona
| | - Edith A Perez
- Center for Breast Health, Mayo Clinic, Jacksonville, Florida
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Kim YJ, Sung D, Oh E, Cho Y, Cho TM, Farrand L, Seo JH, Kim JY. Flubendazole overcomes trastuzumab resistance by targeting cancer stem-like properties and HER2 signaling in HER2-positive breast cancer. Cancer Lett 2018; 412:118-130. [DOI: 10.1016/j.canlet.2017.10.020] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 10/16/2017] [Accepted: 10/16/2017] [Indexed: 12/15/2022]
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Gingras I, Gebhart G, de Azambuja E, Piccart-Gebhart M. HER2-positive breast cancer is lost in translation: time for patient-centered research. Nat Rev Clin Oncol 2017; 14:669-681. [PMID: 28762384 DOI: 10.1038/nrclinonc.2017.96] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
No biomarker beyond HER2 itself, which suffers from a low positive predictive value, has demonstrated clinical utility in breast cancer, despite numerous attempts to improve treatment tailoring for the growing number of anti-HER2 targeted therapies. This prompted us to examine the body of evidence, using a systematic approach, to identify putative predictive biomarkers in HER2-positive breast cancer, and discuss the hitherto failure to address the needs of patients. In the future, it is hoped immune-based biomarkers will predict benefit from anti-HER2 treatments in the neoadjuvant and adjuvant settings. In advanced-stage disease, the quantification of tumour heterogeneity using molecular-imaging technology has generated informative data on the success or failure of the antibody-drug conjugate T-DM1. Treatment tailoring remains a high priority, in cost-constrained health-care systems, but such tailoring will require a dramatic shift in the way translational research is being conducted, with the establishment of large, easily accessible, and well-annotated databases of candidate predictive biomarkers. Single-centre biomarker research should become a thing of the past.
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Affiliation(s)
- Isabelle Gingras
- Department of Hematology and Oncology, Hôpital du Sacré-Coeur de Montréal, 5400 Boulevard Gouin Ouest, H4J 1C5, Montreal, Quebec, Canada
| | - Géraldine Gebhart
- Department of Nuclear Medicine, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B), 1, rue Heger-Bordet, 1000 Brussels, Belgium
| | - Evandro de Azambuja
- Medical Support Team of the Academic Promoting Team (APT), Institut Jules Bordet, Université Libre de Bruxelles (U.L.B), 1, rue Heger-Bordet, 1000 Brussels, Belgium
| | - Martine Piccart-Gebhart
- Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B), 1, rue Heger-Bordet, 1000 Brussels, Belgium
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Veeraraghavan J, De Angelis C, Reis-Filho JS, Pascual T, Prat A, Rimawi MF, Osborne CK, Schiff R. De-escalation of treatment in HER2-positive breast cancer: Determinants of response and mechanisms of resistance. Breast 2017; 34 Suppl 1:S19-S26. [PMID: 28687441 PMCID: PMC6050048 DOI: 10.1016/j.breast.2017.06.022] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Overexpression and/or gene amplification of HER2, a crucial member of the HER family of four receptors, occur in about 15-20% of breast cancers and define an aggressive subtype of the disease. Activated HER homo and heterodimers govern a complex and redundant downstream signaling network that regulates cell survival and metastasis. Despite treatment with effective HER2-targeted therapies, many HER2-positive tumors fail to respond, or initially respond but eventually develop resistance. One of the upfront reasons for this treatment failure is failure to accurately select the tumors that are truly dependent on HER2 for survival and so would benefit the most from HER2-targeted therapy. In these truly HER2-addicted tumors (i.e. physiologically dependent), resistance could be the result of an incomplete inhibition of signaling at the HER receptor layer. In this regard, preclinical and clinical studies have documented the superiority of combination anti-HER2 therapy over single agent therapy to achieve a more comprehensive inhibition of the various HER receptor dimers. HER2 can be further activated or reactivated by mutations or other alterations in HER2 itself, or in other HER family members. Even when a complete and sustained HER inhibition is achieved, resistance to anti-HER therapy can arise by other somewhat dominant mechanisms, including preexisting or emerging alternative signaling pathways such as the estrogen receptor, deregulated downstream signaling components, especially of the PI3K pathway, and the tumor immune microenvironment. Most of the clinical trials that have investigated the efficacy of anti-HER2 therapies took place in the background of aggressive chemotherapy regimens, thus confounding the identification of key factors of resistance to the anti-HER2 treatments. Recent studies, however, have suggested that some HER2-amplified tumors may benefit from anti-HER2 therapy combined with only a single chemotherapy agent or in the absence of any chemotherapy. This de-escalation approach, a promising therapeutic strategy, is currently being explored in the clinic. In this review, we summarize the major molecular determinants that play a crucial role in influencing tumor response and resistance to HER2-targeted therapy, and discuss the growing need for patient stratification in order to facilitate the development of de-escalation strategies using HER2-targeted therapy alone with no chemotherapy.
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Affiliation(s)
- Jamunarani Veeraraghavan
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Carmine De Angelis
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Jorge S Reis-Filho
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Tomás Pascual
- Department of Medical Oncology, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Aleix Prat
- Department of Medical Oncology, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Mothaffar F Rimawi
- Lester & 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
| | - C Kent Osborne
- Lester & 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 Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Rachel Schiff
- Lester & 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 Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
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D'Huyvetter M, De Vos J, Xavier C, Pruszynski M, Sterckx YGJ, Massa S, Raes G, Caveliers V, Zalutsky MR, Lahoutte T, Devoogdt N. 131I-labeled Anti-HER2 Camelid sdAb as a Theranostic Tool in Cancer Treatment. Clin Cancer Res 2017; 23:6616-6628. [PMID: 28751451 DOI: 10.1158/1078-0432.ccr-17-0310] [Citation(s) in RCA: 127] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 05/23/2017] [Accepted: 07/21/2017] [Indexed: 12/25/2022]
Abstract
Purpose: Camelid single-domain antibody-fragments (sdAb) have beneficial pharmacokinetic properties, and those targeted to HER2 can be used for imaging of HER2-overexpressing cancer. Labeled with a therapeutic radionuclide, they may be used for HER2-targeted therapy. Here, we describe the generation of a 131I-labeled sdAb as a theranostic drug to treat HER2-overexpressing cancer.Experimental Design: Anti-HER2 sdAb 2Rs15d was labeled with 131I using [131I]SGMIB and evaluated in vitro Biodistribution was evaluated in two HER2+ murine xenograft models by micro-SPECT/CT imaging and at necropsy, and under challenge with trastuzumab and pertuzumab. The therapeutic potential of [131I]SGMIB-2Rs15d was investigated in two HER2+ tumor mouse models. A single-dose toxicity study was performed in mice using unlabeled [127I]SGMIB-sdAb at 1.4 mg/kg. The structure of the 2Rs15d-HER2 complex was determined by X-ray crystallography.Results: [131I]SGMIB-2Rs15d bound specifically to HER2+ cells (Kd = 4.74 ± 0.39 nmol/L). High and specific tumor uptake was observed in both BT474/M1 and SKOV-3 tumor xenografted mice and surpassed kidney levels by 3 hours. Extremely low uptake values were observed in other normal tissues at all time points. The crystal structure revealed that 2Rs15d recognizes HER2 Domain 1, consistent with the lack of competition with trastuzumab and pertuzumab observed in vivo [131I]SGMIB-2Rs15d alone, or in combination with trastuzumab, extended median survival significantly. No toxicity was observed after injecting [127I]SGMIB-2Rs15d.Conclusions: These findings demonstrate the theranostic potential of [131I]SGMIB-2Rs15d. An initial scan using low radioactive [*I]SGMIB-2Rs15d allows patient selection and dosimetry calculations for subsequent therapeutic [131I]SGMIB-2Rs15d and could thereby impact therapy outcome on HER2+ breast cancer patients. Clin Cancer Res; 23(21); 6616-28. ©2017 AACR.
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Affiliation(s)
- Matthias D'Huyvetter
- In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.
| | - Jens De Vos
- In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.,Camel-IDS NV/SA, Brussels, Belgium
| | - Catarina Xavier
- In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium
| | | | - Yann G J Sterckx
- Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Sam Massa
- Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.,Myeloid Cell Immunology Laboratory, VIB-UGent Center for Inflammation Research, Gent, Belgium
| | - Geert Raes
- Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.,Myeloid Cell Immunology Laboratory, VIB-UGent Center for Inflammation Research, Gent, Belgium
| | - Vicky Caveliers
- In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.,Nuclear Medicine Department, UZ Brussel, Brussels, Belgium
| | - Michael R Zalutsky
- Department of Radiology, Duke University Medical Center, Durham, North Carolina
| | - Tony Lahoutte
- In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.,Nuclear Medicine Department, UZ Brussel, Brussels, Belgium
| | - Nick Devoogdt
- In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium
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Nishimura R, Toh U, Tanaka M, Saimura M, Okumura Y, Saito T, Tanaka T, Teraoka M, Shimada K, Katayama K, Koga T, Kurashita K, Hasegawa S, Todoroki H, Kai Y, Ohi Y, Toyoshima S, Arima N, Mitsuyama S, Tamura K. Role of HER2-Related Biomarkers (HER2, p95HER2, HER3, PTEN, and PIK3CA) in the Efficacy of Lapatinib plus Capecitabine in HER2-Positive Advanced Breast Cancer Refractory to Trastuzumab. Oncology 2017; 93:51-61. [PMID: 28478451 DOI: 10.1159/000468521] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 02/28/2017] [Indexed: 12/19/2022]
Abstract
OBJECTIVE The aim of this study was to investigate the correlation between human epidermal growth factor receptor 2 (HER2)-related biomarkers and the treatment outcomes using lapatinib plus capecitabine (LC) and to evaluate the influence of the estrogen receptor (ER) status in trastuzumab-refractory HER2-positive advanced breast cancer. METHOD Eighty patients were enrolled in this study. Total HER2, p95HER2, and total HER3 expression were quantified using the VeraTag assays. PTEN (phosphatase and tensin homolog) and p95 expression was evaluated using immunohistochemistry and PIK3CA mutation using direct sequencing. RESULTS The response rate to LC was 30%, clinical benefit rate was 51.3%, and the median progression-free survival (PFS) was 174.5 days. ER negativity significantly correlated with higher HER2 and p95HER2. The lower HER2 and PIK3CA mutations were often observed in the nonresponders. A high p95HER2 expression correlated with longer PFS especially in the high HER2- and ER-positive cases. Patients without the PIK3CA mutation showed longer PFS in the same subset. Overall survival after LC significantly correlated with the number of recurrence organs. CONCLUSION LC therapy is effective in trastuzumab-refractory HER2-positive breast cancer. Moreover, the biomarker expression differed depending on ER status, and a high p95HER2 expression and wild-type PIK3CA gene correlated with longer PFS especially in the ER-positive cases.
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Affiliation(s)
- Reiki Nishimura
- Department of Breast Oncology, Kumamoto Shinto General Hospital, Kumamoto, Japan
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HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance. Cancers (Basel) 2017; 9:cancers9050040. [PMID: 28445439 PMCID: PMC5447950 DOI: 10.3390/cancers9050040] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 04/10/2017] [Accepted: 04/21/2017] [Indexed: 12/19/2022] Open
Abstract
HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs) is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% of patients with HER2+ breast tumor develop de novo resistance to trastuzumab, partially due to the loss of expression of HER2 extracellular domain on their tumor cells. This is due to shedding/cleavage of HER2 by metalloproteinases (ADAMs and MMPs). HER2 shedding results in the accumulation of intracellular carboxyl-terminal HER2 (p95HER2), which is a common phenomenon in trastuzumab-resistant tumors and is suggested as a predictive marker for trastuzumab resistance. Up-regulation of the metalloproteinases is a poor prognosis factor and is commonly seen in mesenchymal-like cancer stem cells that are risen during epithelial to mesenchymal transition (EMT) of tumor cells. HER2 cleavage during EMT can explain why secondary metastatic tumors with high percentage of mesenchymal-like cancer stem cells are mostly resistant to trastuzumab but still sensitive to lapatinib. Importantly, many studies report HER2 interaction with oncogenic/stemness signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT and Hedgehog. HER2 overexpression promotes EMT and the emergence of cancer stem cell properties in BC. Increased expression and activation of metalloproteinases during EMT leads to proteolytic cleavage and shedding of HER2 receptor, which downregulates HER2 extracellular domain and eventually increases trastuzumab resistance. Here, we review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives resistance of BC to trastuzumab.
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Lefort S, Thuleau A, Kieffer Y, Sirven P, Bieche I, Marangoni E, Vincent-Salomon A, Mechta-Grigoriou F. CXCR4 inhibitors could benefit to HER2 but not to triple-negative breast cancer patients. Oncogene 2017; 36:1211-1222. [PMID: 27669438 PMCID: PMC5340801 DOI: 10.1038/onc.2016.284] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 06/27/2016] [Accepted: 07/03/2016] [Indexed: 12/16/2022]
Abstract
The CXCR4 receptor and its ligand CXCL12 (also named stromal cell-derived factor 1, SDF1) have a critical role in chemotaxis and homing, key steps in cancer metastasis. Although myofibroblasts expressing CXCL12 are associated with the presence of axillary metastases in HER2 breast cancers (BC), the therapeutic interest of targeting CXCR4/CXCL12 axis in the different BC subtypes remains unclear. Here, we investigate this question by testing antitumor activity of CXCR4 inhibitors in patient-derived xenografts (PDX), which faithfully reproduce human tumor properties. We observed that two CXCR4 inhibitors, AMD3100 and TN14003, efficiently impair tumor growth and metastasis dissemination in both Herceptin-sensitive and Herceptin-resistant HER2 BC. Conversely, blocking CXCR4/CXCL12 pathway in triple-negative (TN) BC does not reduce tumor growth, and can even increase metastatic spread. Moreover, although CXCR4 inhibitors significantly reduce myofibroblast content in all BC subtypes, they decrease angiogenesis only in HER2 BC. Thus, our findings suggest that targeting CXCR4 could provide some therapeutic interest for HER2 BC patients, whereas it has no impact or could even be detrimental for TN BC patients.
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Affiliation(s)
- S Lefort
- Stress and Cancer Laboratory, LNCC Labelized Team, Institut Curie Research Department, 26 rue d'Ulm, 75248 Paris Cedex 05, France
- Inserm, U830, Genetics and Biology of Cancer, Paris, F-75248, France
| | - A Thuleau
- Laboratory of pre-clinical Investigation, Translational Research Department, Institut Curie Research Department, Paris, France
| | - Y Kieffer
- Stress and Cancer Laboratory, LNCC Labelized Team, Institut Curie Research Department, 26 rue d'Ulm, 75248 Paris Cedex 05, France
- Inserm, U830, Genetics and Biology of Cancer, Paris, F-75248, France
| | - P Sirven
- Stress and Cancer Laboratory, LNCC Labelized Team, Institut Curie Research Department, 26 rue d'Ulm, 75248 Paris Cedex 05, France
- Inserm, U830, Genetics and Biology of Cancer, Paris, F-75248, France
| | - I Bieche
- Service de Génétique, Unité de Pharmacogénétique, Institut Curie Hospital Group, Paris, France
| | - E Marangoni
- Laboratory of pre-clinical Investigation, Translational Research Department, Institut Curie Research Department, Paris, France
| | - A Vincent-Salomon
- Department of Pathology Institut Curie Hospital Group, Paris, France
| | - F Mechta-Grigoriou
- Stress and Cancer Laboratory, LNCC Labelized Team, Institut Curie Research Department, 26 rue d'Ulm, 75248 Paris Cedex 05, France
- Inserm, U830, Genetics and Biology of Cancer, Paris, F-75248, France
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Biomarker analysis of the NeoSphere study: pertuzumab, trastuzumab, and docetaxel versus trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel for the neoadjuvant treatment of HER2-positive breast cancer. Breast Cancer Res 2017; 19:16. [PMID: 28183321 PMCID: PMC5299741 DOI: 10.1186/s13058-017-0806-9] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 01/22/2017] [Indexed: 12/29/2022] Open
Abstract
Background NeoSphere showed significantly higher pathologic complete response (pCR) with neoadjuvant pertuzumab, trastuzumab, and docetaxel compared with trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel. We assessed associations between human epidermal growth factor receptor 2 (HER2) pathway-related biomarkers and clinical outcome in response to these regimens. Methods Tumor, serum, and whole blood samples were collected at baseline and post neoadjuvant treatment before surgery. Associations between biomarkers and pCR, and between biomarkers and clinical variables were assessed in the overall and estrogen receptor (ER)-positive and ER-negative populations. Changes in serum marker levels between baseline and post-neoadjuvant treatment were examined. Results No markers were associated with pCR across all groups; however, significant associations were observed for two markers in individual groups. High HER2 was significantly associated with higher pCR rates (P = 0.001) and a significant treatment interaction (P = 0.0236) with pertuzumab, trastuzumab, and docetaxel (odds ratio 2.07, P = 0.01). Low serum transforming growth factor alpha (TGFα) was associated with higher pCR rates with pertuzumab plus trastuzumab (P = 0.04) without a significant treatment interaction. Presence of truncated HER2 did not affect pCR. A non-significant decreased pCR benefit was observed consistently across groups in patients with mutated PIK3CA while the treatment benefit from pertuzumab was maintained when comparing the trastuzumab plus docetaxel and pertuzumab, trastuzumab, and docetaxel groups. Notably, PIK3CA exon 9 mutations were associated with residual disease (pooled groups), which was not found for exon 20 mutations. Serum HER2 extracellular domain levels were significantly increased between baseline and post-neoadjuvant treatment in the non-trastuzumab-treated group, and decreased in the trastuzumab-containing groups (likely due to trastuzumab’s mechanism of action). Differences in biomarker profiles according to ER status were observed. Conclusions The observed associations of HER2 protein levels with sensitivity to pertuzumab, and of PIK3CA exon 9 mutation to lack of sensitivity to HER2-targeted monoclonal antibody treatment, warrant further investigation. Previously reported findings of truncated forms of HER2 as resistance markers to HER2-targeted treatment could not be confirmed in NeoSphere. Conventional HER2 assessment should continue and HER2 remains the only biomarker suitable for patient selection in this population. Trial registration Clinicaltrials.gov, NCT00545688. Registered on 16 October 2007. Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0806-9) contains supplementary material, which is available to authorized users.
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Martinho O, Silva-Oliveira R, Cury FP, Barbosa AM, Granja S, Evangelista AF, Marques F, Miranda-Gonçalves V, Cardoso-Carneiro D, de Paula FE, Zanon M, Scapulatempo-Neto C, Moreira MA, Baltazar F, Longatto-Filho A, Reis RM. HER Family Receptors are Important Theranostic Biomarkers for Cervical Cancer: Blocking Glucose Metabolism Enhances the Therapeutic Effect of HER Inhibitors. Theranostics 2017; 7:717-732. [PMID: 28255362 PMCID: PMC5327645 DOI: 10.7150/thno.17154] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 11/21/2016] [Indexed: 12/17/2022] Open
Abstract
Persistent HPV infection alone is not sufficient for cervical cancer development, which requires additional molecular alterations for tumor progression and metastasis ultimately leading to a lethal disease. In this study, we performed a comprehensive analysis of HER family receptor alterations in cervical adenocarcinoma. We detected overexpression of HER protein, mainly HER2, which was an independent prognostic marker for these patients. By using in vitro and in vivo approaches, we provided evidence that HER inhibitors, allitinib and lapatinib, were effective in reducing cervical cancer aggressiveness. Furthermore, combination of these drugs with glucose uptake blockers could overcome the putative HIF1-α-mediated resistance to HER-targeted therapies. Thus, we propose that the use of HER inhibitors in association with glycolysis blockers can be a potentially effective treatment option for HER-positive cervical cancer patients.
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Affiliation(s)
- Olga Martinho
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Molecular Oncology Research Center (CPOM), Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - Renato Silva-Oliveira
- Molecular Oncology Research Center (CPOM), Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - Fernanda P. Cury
- Molecular Oncology Research Center (CPOM), Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - Ana Martins Barbosa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Sara Granja
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | | | - Fábio Marques
- Department of Pathology of the School of Medicine of the Federal University of Goiás, Brazil
| | - Vera Miranda-Gonçalves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Diana Cardoso-Carneiro
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Flávia E. de Paula
- Molecular Oncology Research Center (CPOM), Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - Maicon Zanon
- Molecular Oncology Research Center (CPOM), Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | | | - Marise A.R. Moreira
- Department of Pathology of the School of Medicine of the Federal University of Goiás, Brazil
| | - Fátima Baltazar
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Adhemar Longatto-Filho
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Molecular Oncology Research Center (CPOM), Barretos Cancer Hospital, Barretos, São Paulo, Brazil
- Laboratory of Medical Investigation (LIM) 14, Faculty of Medicine, São Paulo State University, Brazil
| | - Rui Manuel Reis
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Molecular Oncology Research Center (CPOM), Barretos Cancer Hospital, Barretos, São Paulo, Brazil
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42
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Lv Q, Meng Z, Yu Y, Jiang F, Guan D, Liang C, Zhou J, Lu A, Zhang G. Molecular Mechanisms and Translational Therapies for Human Epidermal Receptor 2 Positive Breast Cancer. Int J Mol Sci 2016; 17:E2095. [PMID: 27983617 PMCID: PMC5187895 DOI: 10.3390/ijms17122095] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 11/15/2016] [Accepted: 12/01/2016] [Indexed: 12/16/2022] Open
Abstract
Breast cancer is the second leading cause of cancer death among women. Human epidermal receptor 2 (HER2) positive breast cancer (HER2+ BC) is the most aggressive subtype of breast cancer, with poor prognosis and a high rate of recurrence. About one third of breast cancer is HER2+ BC with significantly high expression level of HER2 protein compared to other subtypes. Therefore, HER2 is an important biomarker and an ideal target for developing therapeutic strategies for the treatment HER2+ BC. In this review, HER2 structure and physiological and pathological roles in HER2+ BC are discussed. Two diagnostic tests, immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH), for evaluating HER2 expression levels are briefly introduced. The current mainstay targeted therapies for HER2+ BC include monoclonal antibodies, small molecule tyrosine kinase inhibitors, antibody-drug conjugates (ADC) and other emerging anti-HER2 agents. In clinical practice, combination therapies are commonly adopted in order to achieve synergistic drug response. This review will help to better understand the molecular mechanism of HER2+ BC and further facilitate the development of more effective therapeutic strategies against HER2+ BC.
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Affiliation(s)
- Quanxia Lv
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU (Haimen) Institute of Science and Technology (IST), Haimen 226133, China.
| | - Ziyuan Meng
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU (Haimen) Institute of Science and Technology (IST), Haimen 226133, China.
| | - Yuanyuan Yu
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
| | - Feng Jiang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU (Haimen) Institute of Science and Technology (IST), Haimen 226133, China.
- The State Key Laboratory Base of Novel Functional Materials and Preparation Science, Faculty of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China.
| | - Daogang Guan
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
| | - Chao Liang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
| | - Junwei Zhou
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
| | - Aiping Lu
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU (Haimen) Institute of Science and Technology (IST), Haimen 226133, China.
| | - Ge Zhang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU (Haimen) Institute of Science and Technology (IST), Haimen 226133, China.
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43
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Newie I, Søkilde R, Persson H, Jacomasso T, Gorbatenko A, Borg Å, de Hoon M, Pedersen SF, Rovira C. HER2-encoded mir-4728 forms a receptor-independent circuit with miR-21-5p through the non-canonical poly(A) polymerase PAPD5. Sci Rep 2016; 6:35664. [PMID: 27752128 PMCID: PMC5067774 DOI: 10.1038/srep35664] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 10/04/2016] [Indexed: 12/24/2022] Open
Abstract
We previously reported that the human HER2 gene encodes the intronic microRNA mir-4728, which is overexpressed together with its oncogenic host gene and may act independently of the HER2 receptor. More recently, we also reported that the oncogenic miR-21-5p is regulated by 3' tailing and trimming by the non-canonical poly(A) polymerase PAPD5 and the ribonuclease PARN. Here we demonstrate a dual function for the HER2 locus in upregulation of miR-21-5p; while HER2 signalling activates transcription of mir-21, miR-4728-3p specifically stabilises miR-21-5p through inhibition of PAPD5. Our results establish a new and unexpected oncogenic role for the HER2 locus that is not currently being targeted by any anti-HER2 therapy.
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Affiliation(s)
- Inga Newie
- Department of Clinical Sciences, Lund, Division of Oncology and Pathology, Lund University Cancer Center, Lund, Sweden.,BioCARE, Strategic Cancer Research Program, Lund, Sweden
| | - Rolf Søkilde
- Department of Clinical Sciences, Lund, Division of Oncology and Pathology, Lund University Cancer Center, Lund, Sweden.,BioCARE, Strategic Cancer Research Program, Lund, Sweden
| | - Helena Persson
- Department of Clinical Sciences, Lund, Division of Oncology and Pathology, Lund University Cancer Center, Lund, Sweden
| | - Thiago Jacomasso
- Department of Clinical Sciences, Lund, Division of Oncology and Pathology, Lund University Cancer Center, Lund, Sweden
| | - Andrej Gorbatenko
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Åke Borg
- Department of Clinical Sciences, Lund, Division of Oncology and Pathology, Lund University Cancer Center, Lund, Sweden.,BioCARE, Strategic Cancer Research Program, Lund, Sweden.,CREATE Health, Strategic Centre for Translational Cancer Research, Lund, Sweden
| | - Michiel de Hoon
- Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Japan
| | - Stine F Pedersen
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Carlos Rovira
- Department of Clinical Sciences, Lund, Division of Oncology and Pathology, Lund University Cancer Center, Lund, Sweden.,BioCARE, Strategic Cancer Research Program, Lund, Sweden.,CREATE Health, Strategic Centre for Translational Cancer Research, Lund, Sweden
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44
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Afonso SL, Cataneo AJM, de Oliveira Carvalho PE. Lapatinib for advanced breast cancer overexpressing HER2. Hippokratia 2016. [DOI: 10.1002/14651858.cd009713.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Sergio L Afonso
- Marilia Medical School; Evidence Based Health Actions and Oncology; Sperendio Cabrini 295 Marilia Sao Paulo Brazil 17516-300
| | - Antonio José Maria Cataneo
- São Paulo State University; Department of Surgery & Orthopedics; Distrito de Rubião Júnior, s/n São Paulo Brazil 18618-970
| | - Paulo Eduardo de Oliveira Carvalho
- Marilia Medical School; Evidence Based Health Actions Department and Thoracic Surgery Department; Avenida Monte Carmelo, 800 Bairro Fragata Marilia Sao Paulo Brazil 17519-030
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45
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de Melo Gagliato D, Leonardo Fontes Jardim D, Marchesi MSP, Hortobagyi GN. Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer. Oncotarget 2016; 7:64431-64446. [PMID: 26824988 PMCID: PMC5325455 DOI: 10.18632/oncotarget.7043] [Citation(s) in RCA: 148] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Accepted: 01/18/2016] [Indexed: 12/12/2022] Open
Abstract
Breast Cancer (BC) is a highly prevalent disease. A woman living in the United States has a 12.3% lifetime risk of being diagnosed with breast cancer [1]. It is the most common female cancer and the second most common cause of cancer death in women [2]. Of note, amplification or overexpression of Human Epidermal Receptor 2 (HER2) oncogene is present in approximately 18 to 20% of primary invasive breast cancers, and until personalized therapy became available for this specific BC subtype, the worst rates of Overall Survival (OS) and Recurrence-Free Survival (RFS) were observed in the HER2+ BC cohort, compared to all other types, including triple negative BC (TNBC) [3].HER2 is a member of the epidermal growth factor receptor (EGFR) family. Other family members include EGFR or HER1, HER3 and HER4. HER2 can form heterodimers with any of the other three receptors, and is considered to be the preferred dimerization partner of the other HER or ErbB receptors [4]. Phosphorylation of tyrosine residues within the cytoplasmic domain is the result of receptor dimerization and culminates into initiation of a variety of signalling pathways involved in cellular proliferation, transcription, motility and apoptosis inhibition [5].In addition to being an important prognostic factor in women diagnosed with BC, HER2 overexpression also identifies those patients who benefit from treatment with agents that target HER2, such as trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1) and small molecules tyrosine kinase inhibitors of HER2 [6, 11, 127].In fact, trastuzumab altered the natural history of patients diagnosed with HER2+ BC, both in early and metastatic disease setting, in a major way [8-10]. Nevertheless, there are many women that will eventually develop metastatic disease, despite being treated with anti-HER2 therapy in the early disease setting. Moreover, advanced tumors may reach a point where no anti-HER2 treatment will achieve disease control, including recently approved drugs, such as T-DM1.This review paper will concentrate on major biological pathways that ultimately lead to resistance to anti-HER2 therapies in BC, summarizing their mechanisms. Strategies to overcome this resistance, and the rationale involved in each tactics to revert this scenario will be presented to the reader.
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46
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Novotny CJ, Pollari S, Park JH, Lemmon MA, Shen W, Shokat KM. Overcoming resistance to HER2 inhibitors through state-specific kinase binding. Nat Chem Biol 2016; 12:923-930. [PMID: 27595329 PMCID: PMC5069157 DOI: 10.1038/nchembio.2171] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 06/16/2016] [Indexed: 12/14/2022]
Abstract
The heterodimeric receptor tyrosine kinase complex formed by HER2 and HER3 can act as an oncogenic driver and is also responsible for rescuing a large number of cancers from a diverse set of targeted therapies. Current inhibitors of these proteins, particularly HER2, have dramatically improved patient outcomes in the clinic but recent studies have demonstrated that stimulation of the heterodimeric complex, either by growth factors or increasing the concentrations of HER2 and HER3 at the membrane, significantly diminishes their activity. In order to find an inhibitor of the active HER2/HER3 oncogenic complex we developed a panel of Ba/F3 cell lines suitable for ultra-high throughput screening. Medicinal chemistry on the hit scaffold resulted in a novel inhibitor that acts through the preferential inhibition of the active state of HER2 and as a result is able to overcome cellular mechanisms of resistance such as growth factors or mutations that stabilize the active form of HER2.
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Affiliation(s)
- Chris J Novotny
- Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California, USA.,Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA
| | - Sirkku Pollari
- California Institute for Biomedical Research (Calibr), La Jolla, California, USA
| | - Jin H Park
- Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.,Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Mark A Lemmon
- Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.,Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Weijun Shen
- California Institute for Biomedical Research (Calibr), La Jolla, California, USA
| | - Kevan M Shokat
- Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California, USA.,Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA
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47
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Gu S, Hu Z, Ngamcherdtrakul W, Castro DJ, Morry J, Reda MM, Gray JW, Yantasee W. Therapeutic siRNA for drug-resistant HER2-positive breast cancer. Oncotarget 2016; 7:14727-41. [PMID: 26894975 PMCID: PMC4924747 DOI: 10.18632/oncotarget.7409] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 01/30/2016] [Indexed: 01/18/2023] Open
Abstract
HER2 is overexpressed in about 20% of breast cancers and contributes to poor prognosis. Unfortunately, a large fraction of patients have primary or acquired resistance to the HER2-targeted therapy trastuzumab, thus a multi-drug combination is utilized in the clinic, putting significant burden on patients. We systematically identified an optimal HER2 siRNA from 76 potential sequences and demonstrated its utility in overcoming intrinsic and acquired resistance to trastuzumab and lapatinib in 18 HER2-positive cancer cell lines. We provided evidence that the drug-resistant cancer maintains dependence on HER2 for survival. Importantly, cell lines did not readily develop resistance following extended treatment with HER2 siRNA. Using our recently developed nanoparticle platform, systemic delivery of HER2 siRNA to trastuzumab-resistant tumors resulted in significant growth inhibition. Moreover, the optimal HER2 siRNA could also silence an exon 16 skipped HER2 splice variant reported to be highly oncogenic and linked to trastuzumab resistance.
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Affiliation(s)
- Shenda Gu
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, 97239, USA
| | - Zhi Hu
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, 97239, USA
| | - Worapol Ngamcherdtrakul
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, 97239, USA
- PDX Pharmaceuticals, LLC, Portland, Oregon, 97239, USA
| | - David J. Castro
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, 97239, USA
- PDX Pharmaceuticals, LLC, Portland, Oregon, 97239, USA
| | - Jingga Morry
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, 97239, USA
| | - Moataz M. Reda
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, 97239, USA
| | - Joe W. Gray
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, 97239, USA
| | - Wassana Yantasee
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, 97239, USA
- PDX Pharmaceuticals, LLC, Portland, Oregon, 97239, USA
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48
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Karamouzis MV, Dalagiorgou G, Georgopoulou U, Nonni A, Kontos M, Papavassiliou AG. HER-3 targeting alters the dimerization pattern of ErbB protein family members in breast carcinomas. Oncotarget 2016; 7:5576-5597. [PMID: 26716646 PMCID: PMC4868707 DOI: 10.18632/oncotarget.6762] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2015] [Accepted: 12/22/2015] [Indexed: 01/06/2023] Open
Abstract
Breast carcinogenesis is a multi-step process in which membrane receptor tyrosine kinases are crucial participants. Lots of research has been done on epidermal growth factor receptor (EGFR) and HER-2 with important clinical results. However, breast cancer patients present intrinsic or acquired resistance to available HER-2-directed therapies, mainly due to HER-3. Using new techniques, such as proximity ligation assay, herein we evaluate the dimerization pattern of HER-3 and the importance of context-dependent dimer formation between HER-3 and other HER protein family members. Additionally, we show that the efficacy of novel HER-3 targeting agents can be better predicted in certain breast cancer patient sub-groups based on the dimerization pattern of HER protein family members. Moreover, this model was also evaluated and reproduced in human paraffin-embedded breast cancer tissues.
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Affiliation(s)
- Michalis V Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Georgia Dalagiorgou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Urania Georgopoulou
- Laboratory of Molecular Virology, Hellenic Pasteur Institute, 11521 Athens, Greece
| | - Afroditi Nonni
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michalis Kontos
- Department of Propaedeutic Surgery, Medical School, National and Kapodistrian University of Athens, 'Laikon' General Hospital, 11527 Athens, Greece
| | - Athanasios G Papavassiliou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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49
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Wilson JN, Liu W, Brown AS, Landgraf R. Binding-induced, turn-on fluorescence of the EGFR/ERBB kinase inhibitor, lapatinib. Org Biomol Chem 2015; 13:5006-11. [PMID: 25820099 DOI: 10.1039/c5ob00239g] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
We report the photophysical properties, binding-induced turn-on emission, and fluorescence imaging of the cellular uptake and distribution of lapatinib, an EGFR/ERBB inhibitor. Lapatinib, a type II, i.e. inactive state, inhibitor that targets the ATP binding pocket of the EGFR family of receptor tyrosine kinases. DFT calculations predict that the 6-furanylquinazoline core of lapatinib should exhibit an excited state with charge transfer character and an S0 to S1 transition energy of 3.4 eV. Absorption confirms an optical transition in the near UV to violet, while fluorescence spectroscopy shows that photoemission is highly sensitive to solvent polarity. The hydrophobicity of lapatinib leads to fluorescent aggregates in solution, however, binding to the lipid-carrier protein, BSA or to the kinase domain of ERBB2, produces spectroscopically distinct photoemission. Confocal fluorescence microscopy imaging of lapatinib uptake in ERBB2-overexpressing MCF7 and BT474 cells reveals pools of intracellular inhibitor with emission profiles consistent with aggregated lapatinib.
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Affiliation(s)
- James N Wilson
- Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, Florida 33124, USA.
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50
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Wang H, DeGnore JP, Kelly BD, True J, Garsha K, Bieniarz C. A technique for relative quantitation of cancer biomarkers in formalin-fixed, paraffin-embedded (FFPE) tissue using stable-isotope-label based mass spectrometry imaging (SILMSI). JOURNAL OF MASS SPECTROMETRY : JMS 2015; 50:1088-1095. [PMID: 28338251 DOI: 10.1002/jms.3623] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Revised: 05/08/2015] [Accepted: 05/16/2015] [Indexed: 06/06/2023]
Abstract
We developed a novel technique for the relative quantitation of pairs of cancer biomarkers in formalin-fixed paraffin-embedded (FFPE) tissue. The method utilizes stable isotope labeled (SIL) chromogens deposited during the standard immunohistochemistry (IHC) tissue staining process. The labeled chromogens are precipitated on tissue enzymatically using the standard IHC protocols. The tissue is then imaged with matrix-free laser desorption ionization time-of-flight mass spectrometry, and peak intensities of reporter ions are used to estimate the relative quantitation of protein biomarkers across the tissue. The relative abundance of two breast cancer biomarkers, estrogen receptor (ER) and progesterone receptor (PgR), were quantitated using their ratio of expression in xenograft models, and the ratios were found to be reproducible both within and across serial sections. The relative quantification of multiple biomarkers in situ across a single tissue section adds an additional dimension in cancer histological evaluation by allowing a visual and statistical assessment of tumor heterogeneity. Copyright © 2015 John Wiley & Sons, Ltd.
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Affiliation(s)
- Hong Wang
- Clinical Cancer Prevention, MD Anderson Cancer Center, 6767 Bertner Ave., Houston, TX, 77030, USA
| | - Jon P DeGnore
- Ventana Medical Systems, Inc., 1910 E. Innovation Park Drive, Tucson, AZ, 85755, USA
| | - Brian D Kelly
- Ventana Medical Systems, Inc., 1910 E. Innovation Park Drive, Tucson, AZ, 85755, USA
| | - Jan True
- Ventana Medical Systems, Inc., 1910 E. Innovation Park Drive, Tucson, AZ, 85755, USA
| | - Karl Garsha
- Ventana Medical Systems, Inc., 1910 E. Innovation Park Drive, Tucson, AZ, 85755, USA
| | - Christopher Bieniarz
- Ventana Medical Systems, Inc., 1910 E. Innovation Park Drive, Tucson, AZ, 85755, USA
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