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Baez-Navarro X, Groenendijk FH, Oudijk L, von der Thüsen J, Fusco N, Curigliano G, van Deurzen CHM. HER2-low across solid tumours: different incidences and definitions. Pathology 2025; 57:403-414. [PMID: 40221332 DOI: 10.1016/j.pathol.2025.02.003] [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: 11/05/2024] [Revised: 01/22/2025] [Accepted: 02/10/2025] [Indexed: 04/14/2025]
Abstract
Antibody-drug conjugates, particularly trastuzumab deruxtecan (T-DXd), have emerged as effective therapies for various solid tumours. Clinical trials show that T-DXd improves survival in both HER2-positive and HER2-low breast cancer patients. Additionally, it improves survival in HER2-positive gastro-oesophageal cancer and elicits objective responses in HER2-low tumours. Responses have also been noted in lung and gynaecological cancers with HER2 expression, although subgroup analyses for HER2-low cases are lacking. This review assesses HER2 protein expression levels and gene amplification across solid tumours where T-DXd shows potential benefits. We focus on the accuracy and limitations of HER2 testing methods, particularly for identifying HER2-low cancer. A semi-systematic approach was employed, searching EMBASE, Medline, Cochrane, and PubMed databases. We calculated median incidences of HER2-positive, HER2-low, and HER2-0 by immunohistochemistry (IHC), and HER2 amplification by in situ hybridisation (ISH). A total of 144 studies were included, covering breast (n=57), gastro-oesophageal (n=33), lung (n=17), gynaecological (n=24), and various other carcinomas (n=13). The median incidences of HER2-low were 52%, 16%, 58%, and 17% in breast, gastro-oesophageal, endometrial, and ovarian cancers, respectively, with unknown incidences in lung and cervical cancers. Factors influencing HER2-low detection include tumour heterogeneity, antibody clones, observer variability, and lack of validated scoring criteria. Given the significant proportion of HER2-low cases, many patients could benefit from T-DXd, but limitations in detection accuracy necessitate further research and standardisation in diagnostic methods and criteria to advance the clinical utility of T-DXd for HER2-low tumours.
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Affiliation(s)
- Ximena Baez-Navarro
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
| | | | - Lindsey Oudijk
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Jan von der Thüsen
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Nicola Fusco
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy; Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy
| | - Giuseppe Curigliano
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy; Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
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Hou Y, Xue X, Zhang Z, Mai D, Luo W, Zhou M, Liu Z, Huang Y. Genomic and clinical characterization of HER2 exon 20 mutations in non-small cell lung cancer: insights from a multicenter study in South China. BMC Cancer 2025; 25:752. [PMID: 40264034 PMCID: PMC12012961 DOI: 10.1186/s12885-025-14125-9] [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: 12/05/2024] [Accepted: 04/09/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND The objective of this study was to investigate the clinical and genetic characteristics and clinical relevance of HER2 exon 20 oncogenic variants in non-small cell lung cancer (NSCLC) patients. METHODS This prospective study analyzed 51 NSCLC patients with HER2 mutations, identified via next-generation sequencing (NGS) of tissue, blood, cerebrospinal fluid, or pleural effusion samples. Patients were grouped based on the presence of exon 20 mutations (exon 20 vs. non-exon 20) and further divided based on whether they had received prior anti-tumor treatments (baseline vs. non-baseline). Clinical and genetic data, treatment responses were analyzed. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier methods and compared with log-rank tests. Gene ontology (GO) analysis was performed to uncover the biological significance of the mutated genes. RESULTS In a cohort of 651 NSCLC patients, 51 (7.83%) harbored HER2 alterations, including 20 (3.08%) with exon 20 mutations. The median age of the HER2-altered subgroup was 58.5 years. Adenocarcinoma was the most prevalent subtype (96.1%), and most patients presented at stage IV (72.5%). The most common metastatic sites were the lungs (68.6%), lymph nodes (52.9%), and brain (43.1%). Among the HER2 mutated patients, 20 (39.3%) had exon 20 mutations. Exon 20 mutations were more prevalent in the non-baseline group (55.0% vs. 29.0%, P = 0.049) and males (75.0%, P = 0.025). These mutations were associated with a higher rate of metastasis to the lungs, lymph nodes (P < 0.001). Patients with exon 20 mutations demonstrated poorer overall survival (OS) outcomes (P = 0.048). No significant differences were observed in age, smoking history, histological subtype, or TNM stage at diagnosis between groups. The majority of exon 20 mutations were in-frame indel mutations (92.0%), with the most common specific mutation being p.Y772_A775dup (70%). Gene Ontology (GO) analysis linked exon 20 mutations to unregulated protein kinase activity and anoikis. CONCLUSIONS Our study found that NSCLC patients with HER2 exon 20 oncogenic variants have a higher risk of metastasis and drug resistance, leading to worse outcomes than non-exon 20 mutations. This highlights the urgent need for targeted therapies aimed at exon 20 insertions to improve survival and treatment outcomes in this subgroup.
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Affiliation(s)
- Yating Hou
- Department of Oncology, Maoming People's Hospital, 101 Weimin Road, Maoming, 525000, Guangdong, China
| | - Xingyang Xue
- Department of Thoracic Surgery and Oncology, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, National Clinical Research Centre for Respiratory Disease, Guangzhou, China
| | - Zhuoyun Zhang
- Department of Oncology, Maoming People's Hospital, 101 Weimin Road, Maoming, 525000, Guangdong, China
| | - Dahai Mai
- Department of Oncology, Maoming People's Hospital, 101 Weimin Road, Maoming, 525000, Guangdong, China
| | - Wei Luo
- Department of Oncology, Maoming People's Hospital, 101 Weimin Road, Maoming, 525000, Guangdong, China
| | - Mingyu Zhou
- Department of Oncology, Maoming People's Hospital, 101 Weimin Road, Maoming, 525000, Guangdong, China
| | - Zichuan Liu
- Internal Medicine Section 2, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, Guangdong, China.
| | - Yisheng Huang
- Department of Oncology, Maoming People's Hospital, 101 Weimin Road, Maoming, 525000, Guangdong, China.
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Tasnim M, Wahlquist P, Hill JT. Zebrafish: unraveling genetic complexity through duplicated genes. Dev Genes Evol 2024; 234:99-116. [PMID: 39079985 PMCID: PMC11612004 DOI: 10.1007/s00427-024-00720-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 07/19/2024] [Indexed: 12/06/2024]
Abstract
The zebrafish is an invaluable model organism for genetic, developmental, and disease research. Although its high conservation with humans is often cited as justification for its use, the zebrafish harbors oft-ignored genetic characteristics that may provide unique insights into gene structure and function. Zebrafish, along with other teleost fish, underwent an additional round of whole genome duplication after their split from tetrapods-resulting in an abundance of duplicated genes when compared to other vertebrates. These duplicated genes have evolved in distinct ways over the ensuing 350 million years. Thus, each gene within a duplicated gene pair has nuanced differences that create a unique identity. By investigating both members of the gene pair together, we can elucidate the mechanisms that underly protein structure and function and drive the complex interplay within biological systems, such as signal transduction cascades, genetic regulatory networks, and evolution of tissue and organ function. It is crucial to leverage such studies to explore these molecular dynamics, which could have far-reaching implications for both basic science and therapeutic development. Here, we will review the role of gene duplications and the existing models for gene divergence and retention following these events. We will also highlight examples within each of these models where studies comparing duplicated genes in the zebrafish have yielded key insights into protein structure, function, and regulation.
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Affiliation(s)
- Maliha Tasnim
- Department of Cell Biology and Physiology, Brigham Young University, 701 E. University Pkwy, Provo, UT, 84602, USA
| | - Preston Wahlquist
- Department of Cell Biology and Physiology, Brigham Young University, 701 E. University Pkwy, Provo, UT, 84602, USA
| | - Jonathon T Hill
- Department of Cell Biology and Physiology, Brigham Young University, 701 E. University Pkwy, Provo, UT, 84602, USA.
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Sun C, Zhang Y, Wang Z, Chen J, Zhang J, Gu Y. TMED2 promotes glioma tumorigenesis by being involved in EGFR recycling transport. Int J Biol Macromol 2024; 262:130055. [PMID: 38354922 DOI: 10.1016/j.ijbiomac.2024.130055] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 01/22/2024] [Accepted: 02/06/2024] [Indexed: 02/16/2024]
Abstract
Aberrant epidermal growth factor receptor (EGFR) signaling is the core signaling commonly activated in glioma. The transmembrane emp24 protein transport domain protein 2 (TMED2) interacts with cargo proteins involved in protein sorting and transport between endoplasmic reticulum (ER) and Golgi apparatus. In this study, we found the correlation between TMED2 with glioma progression and EGFR signaling through database analysis. Moreover, we demonstrated that TMED2 is essential for glioma cell proliferation, migration, and invasion at the cellular levels, as well as tumor formation in mouse models, underscoring its significance in the pathobiology of gliomas. Mechanistically, TMED2 was found to enhance EGFR-AKT signaling by facilitating EGFR recycling, thereby providing the initial evidence of TMED2's involvement in the membrane protein recycling process. In summary, our findings shed light on the roles and underlying mechanisms of TMED2 in the regulation of glioma tumorigenesis and EGFR signaling, suggesting that targeting TMED2 could emerge as a promising therapeutic strategy for gliomas and other tumors associated with aberrant EGFR signaling.
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Affiliation(s)
- Changning Sun
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; College of Marine Science and Biological Engineering, Qingdao University of Science and Technology, Qingdao 266042, China; Laboratory for Marine Drugs and Bioproducts of Laoshan Laboratory, Qingdao 266200, China
| | - Yihan Zhang
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts of Laoshan Laboratory, Qingdao 266200, China
| | - Zhuangzhi Wang
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; College of Marine Science and Biological Engineering, Qingdao University of Science and Technology, Qingdao 266042, China; Laboratory for Marine Drugs and Bioproducts of Laoshan Laboratory, Qingdao 266200, China
| | - Jin Chen
- College of Marine Science and Biological Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
| | - Junhua Zhang
- College of Marine Science and Biological Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
| | - Yuchao Gu
- College of Marine Science and Biological Engineering, Qingdao University of Science and Technology, Qingdao 266042, China; Laboratory for Marine Drugs and Bioproducts of Laoshan Laboratory, Qingdao 266200, China.
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Nützinger J, Bum Lee J, Li Low J, Ling Chia P, Talisa Wijaya S, Chul Cho B, Min Lim S, Soo RA. Management of HER2 alterations in non-small cell lung cancer - The past, present, and future. Lung Cancer 2023; 186:107385. [PMID: 37813015 DOI: 10.1016/j.lungcan.2023.107385] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 09/21/2023] [Accepted: 09/22/2023] [Indexed: 10/11/2023]
Abstract
HER2 mutations, which account for 2-4% of non-small cell lung cancer (NSCLC), are distinct molecular alterations identified via next generation sequencing (NGS). Previously, treatment outcomes in HER2-mutant metastatic NSCLC were dismal, showing limited clinical benefit with platinum-based chemotherapy with or without immunotherapy. In contrast to HER2-altered breast and gastric cancer, HER2-mutant NSCLC does not benefit from HER2 targeting agents such as trastuzumab or TDM1. HER2 mutations are also inherently different from HER2 overexpression and amplification. Currently, trastuzumab deruxtecan, a HER2 targeting antibody drug conjugate (ADC) is the first and only approved treatment option for patients with HER2-mutant metastatic NSCLC after failure with standard treatment. In this review, we summarized the biology of HER2 and detection of HER2 overexpression, amplification and mutations, as well as general landscape of landmark and ongoing clinical trials encompassing from chemotherapy to targeted agents, including tyrosine kinase inhibitors (TKIs), ADCs and investigational agents.
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Affiliation(s)
- Jorn Nützinger
- Department of Haematology-Oncology, National University Cancer Institute, Singapore
| | - Jii Bum Lee
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Jia Li Low
- Department of Haematology-Oncology, National University Cancer Institute, Singapore
| | - Puey Ling Chia
- Department of Medical Oncology, Tan Tock Seng Hospital, Singapore
| | | | - Byoung Chul Cho
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Sun Min Lim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Ross A Soo
- Department of Haematology-Oncology, National University Cancer Institute, Singapore.
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Abu Al Karsaneh O, Al Anber A, ALQudah M, Al-Mustafa S, AlMa'aitah H, Sughayer M. Prevalence and clinicopathological associations of HER2 expression in non-small cell lung cancer: a retrospective study in Jordanian patients. Diagn Pathol 2023; 18:75. [PMID: 37340403 DOI: 10.1186/s13000-023-01364-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 06/12/2023] [Indexed: 06/22/2023] Open
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2), a promising therapeutic target, can be mutated, amplified, or overexpressed in different malignancies, including non-small cell lung cancer (NSCLC). Although these alterations showed adverse prognostic effects in many cancers, their clinical significance in NSCLC is controversial. This study primarily assessed the prevalence of HER2 protein expression in NSCLC among Jordanian patients. In addition, the possible association between HER2 protein expression and clinicopathological variables was evaluated. METHODS A total of 100 surgically resected NSCLC cases treated at King Hussein Cancer Center (KHCC) between 2009 and 2021 were examined for HER2 protein expression using immunohistochemistry (IHC). The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for breast cancer were applied to interpret the results with a final score ranging from 0 to 3+, considering a score of 3 + as overexpression. Additionally, a separate subset of patients was tested for HER2 gene mutation. Fisher's exact test was used to assess the association between HER2 scores and the other variables. Kaplan-Meier method was used to calculate survival. RESULTS Of the 100 cases, Her2 overexpression (score 3+) was detected in 2 cases (2%), score 2 + in 10 cases (10%), score 1 + in 12 cases (12%), and score 0 in 76 cases (76%). The two positive cases were one adenocarcinoma and one squamous cell carcinoma; both patients were elderly male smokers. No significant association was identified between Her2 expression and age, gender, smoking, histological subtype, grade, stage, tumor size, and lymph node status. Our findings also showed no association between Her2 expression and survival; however, advanced tumor stages and positive lymph node metastasis were significantly associated with poor overall survival. All cases tested for the Her2 mutation were negative. CONCLUSIONS Her2 overexpression is uncommon in NSCLC among the Jordanian population. However, when the same scoring criteria are used, the rates are similar to other results found in Asian cohorts. Due to our study's relatively small sample size, a larger one is required to investigate the prognostic value and the molecular associations between the different Her2 alterations.
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Affiliation(s)
- Ola Abu Al Karsaneh
- Department of Microbiology, Pathology and Forensic Medicine, Faculty of Medicine, The Hashemite University, Zarqa, 13133, Jordan
| | - Arwa Al Anber
- Department of Pharmacology and Public Health, Faculty of Medicine, The Hashemite University, Zarqa, 13133, Jordan
| | - Mohammad ALQudah
- Department of Microbiology, Pathology and Forensic Medicine, Faculty of Medicine, The Hashemite University, Zarqa, 13133, Jordan
| | - Sahar Al-Mustafa
- Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Hussien AlMa'aitah
- Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Maher Sughayer
- Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan.
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Ganti AK, Rothe M, Mangat PK, Garrett-Mayer E, Dib EG, Duvivier HL, Ahn ER, Behl D, Borghaei H, Balmanoukian AS, Gaba A, Li R, Osei-Boateng K, Thota R, Grantham GN, Gregory A, Halabi S, Schilsky RL. Pertuzumab Plus Trastuzumab in Patients With Lung Cancer With ERBB2 Mutation or Amplification: Results From the Targeted Agent and Profiling Utilization Registry Study. JCO Precis Oncol 2023; 7:e2300041. [PMID: 37315265 DOI: 10.1200/po.23.00041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/09/2023] [Accepted: 04/19/2023] [Indexed: 06/16/2023] Open
Abstract
PURPOSE The Targeted Agent and Profiling Utilization Registry Study is a pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations. Data from a cohort of patients with lung cancer and ERBB2 mutation or amplification treated with pertuzumab plus trastuzumab (P + T) are reported. METHODS Eligible patients had advanced lung cancer of any histology, no standard treatment options, measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and tumors with ERBB2 mutation or amplification. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) per RECIST v. 1.1 or stable disease (SD) of at least 16 weeks duration (SD16+). Secondary end points included safety, duration of response, duration of SD, progression-free survival, and overall survival. RESULTS Twenty-eight patients with lung cancer (27 non-small-cell, 1 small-cell) and ERBB2 mutation (n = 15), ERBB2 amplification (n = 12), or both (n = 1) were enrolled from November 2016 to July 2020. All patients were evaluable for efficacy and toxicity. Three patients with partial response (two ERBB2 mutation; one both mutation and amplification) and seven patients with SD16+ (five ERBB2 mutation; two amplification) were observed for a DC rate of 37% (95% CI, 21 to 50; P = .005) and OR rate of 11% (95% CI, 2 to 28). Five patients had one or more grade 3 or 4 adverse or serious adverse events at least possibly related to P + T. CONCLUSION Combination P + T showed evidence of antitumor activity in heavily pretreated patients with non-small-cell lung cancer and ERBB2 mutation or amplification, particularly those with ERBB2 exon 20 insertion mutations.
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Affiliation(s)
- Apar K Ganti
- University of Nebraska Medical Center and VA-NWIHCS, Omaha, NE
| | - Michael Rothe
- American Society of Clinical Oncology, Alexandria, VA
| | - Pam K Mangat
- American Society of Clinical Oncology, Alexandria, VA
| | | | - Elie G Dib
- Michigan Cancer Research Consortium, Ypsilanti, MI
| | - Herbert L Duvivier
- Cancer Treatment Centers of America-Atlanta, part of City of Hope, Newnan, GA
| | - Eugene R Ahn
- Cancer Treatment Centers of America-Chicago, part of City of Hope, Zion, IL
| | - Deepti Behl
- Sutter Sacramento Medical Center, Sacramento, CA
| | | | - Ani S Balmanoukian
- The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate, Los Angeles, CA
| | | | - Rui Li
- Providence Portland Medical Center, Providence Cancer Institute, Portland, OR
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Vathiotis IA, Charpidou A, Gavrielatou N, Syrigos KN. HER2 Aberrations in Non-Small Cell Lung Cancer: From Pathophysiology to Targeted Therapy. Pharmaceuticals (Basel) 2021; 14:1300. [PMID: 34959700 PMCID: PMC8705364 DOI: 10.3390/ph14121300] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/06/2021] [Accepted: 12/10/2021] [Indexed: 12/17/2022] Open
Abstract
While human epidermal growth factor receptor 2 (HER2) aberrations have long been described in patients with non-small cell lung cancer (NSCLC), they have only recently been effectively targeted. Unlike patients with breast cancer, NSCLC patients can harbor either HER2-activating mutations or HER2 amplification coupled with protein overexpression. The latter has also been the case for patients with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). As preclinical data continue to accumulate, clinical trials evaluating novel agents that target HER2 have produced promising preliminary results. Here, we review existing data on HER2 aberrations in NSCLC. Starting from HER2 biology in normal and disease processes, we summarize discrepancies in HER2 diagnostic assays between breast cancer and NSCLC. Finally, to dissect the therapeutic implications of HER2-activating mutations versus gene amplification and/or protein overexpression, we present data from prospective clinical trials that have employed distinct classes of agents to target HER2 in patients with NSCLC.
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Affiliation(s)
- Ioannis A. Vathiotis
- Section of Medical Oncology, Third Department of Internal Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.C.); (K.N.S.)
- Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA;
| | - Andriani Charpidou
- Section of Medical Oncology, Third Department of Internal Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.C.); (K.N.S.)
| | - Niki Gavrielatou
- Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA;
| | - Konstantinos N. Syrigos
- Section of Medical Oncology, Third Department of Internal Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.C.); (K.N.S.)
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Nagasaka M, Singh V, Baca Y, Sukari A, Kim C, Mamdani H, Spira AI, Uprety D, Bepler G, Kim ES, Raez LE, Pai SG, Ikpeazu C, Oberley M, Feldman R, Xiu J, Korn WM, Wozniak AJ, Borghaei H, Liu SV. The Effects of HER2 Alterations in EGFR Mutant Non-small Cell Lung Cancer. Clin Lung Cancer 2021; 23:52-59. [PMID: 34801409 DOI: 10.1016/j.cllc.2021.08.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/23/2021] [Accepted: 08/25/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND HER2 alteration (mutation and/or amplification) is associated with poor survival in NSCLC and can mediate resistance to EGFR tyrosine kinase inhibitors. METHODS We retrospectively analyzed de-identified molecular information from 12,946 NSCLC samples that underwent next-generation sequencing (NGS) with Caris Life Sciences. The objectives were to determine the prevalence and type of HER2 alterations with and without EGFR as a co-mutation. Insurance claims were utilized to obtain outcomes data. RESULTS Three hundred and twenty-one patients (2.5%) had HER2 alteration: mutation in 197 patients and amplification in 134. Median age was 65 years and 62% were female. A total of 84% were adenocarcinoma. HER2 exon 20 insertion was most common (69%). A total of 1551 (12%) patients had EGFR mutations. Among samples with EGFR mutations, 24 (1.5%) had concurrent HER2 alteration (8 with HER2 mutation and 16 with amplification). Among 8 patients who had both EGFR and HER2 mutations, 3 had EGFR exon 19 deletions and exon 8 HER2 mutation (S310F). One-third of the patients (7/21) with HER2 extracellular domain (ECD) mutation had co-occurring EGFR mutations. All 7 were S310. Patients with concurrent EGFR mutation and HER2 amplification had longer median time on treatment with EGFR TKI(s) than those with EGFR mutation without HER2 amplification (HR 2.284, P =.004). CONCLUSION A minority of NSCLC samples with EGFR mutations had HER2 alterations. In patients with both mutations, exon 21 mutations for EGFR and exon 8 mutations for HER2 were common. It will be critical to continue to accumulate valuable clinical data for further real-world outcomes analysis.
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Affiliation(s)
- Misako Nagasaka
- Karmanos Cancer Institute/Wayne State University, Detroit, MI; St Marianna University School of Medicine, Kawasaki, Japan.
| | - Vijendra Singh
- Karmanos Cancer Institute/Wayne State University, Detroit, MI
| | | | - Ammar Sukari
- Karmanos Cancer Institute/Wayne State University, Detroit, MI
| | - Chul Kim
- Georgetown University, Washington, DC
| | - Hirva Mamdani
- Karmanos Cancer Institute/Wayne State University, Detroit, MI
| | | | - Dipesh Uprety
- Karmanos Cancer Institute/Wayne State University, Detroit, MI
| | - Gerold Bepler
- Karmanos Cancer Institute/Wayne State University, Detroit, MI
| | - Edward S Kim
- City of Hope Comprehensive Cancer Center, Duarte, CA
| | - Luis E Raez
- Memorial Cancer Institute, Florida International University, Miami, FL
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Clinicopathologic features and treatment advances in cancers with HER2 alterations. Biochim Biophys Acta Rev Cancer 2021; 1876:188605. [PMID: 34358635 DOI: 10.1016/j.bbcan.2021.188605] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/28/2021] [Accepted: 07/28/2021] [Indexed: 12/14/2022]
Abstract
HER2 is one of the most important proteins of the epidermal growth factor receptor (EGFR) family, whose alterations include amplification, overexpression and gene mutation. Growing attention has been given to HER2 as a biomarker for prognosis, an indicator for treatment response and a target for new drugs. Tumors with HER2 alterations have been well studied in multiple locations as distinct entities for treatment, especially breast cancer, gastric cancer, lung cancer and colorectal cancer. These four cancers are the leading causes of cancer incidence and cancer-related death worldwide. The present study details the landscape of HER2 amplification/overexpression and mutations and gives an up-to-date analysis of current clinical trials in the four cancers mentioned above. Different HER2-altered cancers not only respond differently to HER2-targeting therapies but also display diverse survival outcomes. Even in the same type of cancer, HER2 amplification/overexpression differs from HER2 mutation in terms of clinicopathologic features and treatment strategies. As an emerging strategy in cancer treatment, immune checkpoint inhibitors demonstrate distinct outcomes in HER2-altered breast cancer, gastric cancer and lung cancer.
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11
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Wu R, Yuan B, Li C, Wang Z, Song Y, Liu H. A narrative review of advances in treatment and survival prognosis of HER2-positive malignant lung cancers. J Thorac Dis 2021; 13:3708-3720. [PMID: 34277062 PMCID: PMC8264687 DOI: 10.21037/jtd-20-3265] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 04/14/2021] [Indexed: 12/15/2022]
Abstract
Human epidermal growth factor receptor 2 (HER2), as a receptor tyrosine kinase of EGF receptor family, whose mutation is often associated with even if less frequency but poor prognosis and shorter survival in pulmonary malignant tumor. HER2 status include mutation, overexpression, amplification and also some rare genotypes, detected by next generation sequencing (NGS), immunohistochemistry (IHC), and also fluorescence in situ hybridization (FISH). Different genotypes represent different therapeutic targets and indicate different clinical prognosis concluded by previous studies. Unfortunately, no standard guidelines for first-line treatment are widely recognized, and current therapeutic schedules include chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Especially for patients with advanced metastasis, chemotherapy is based as a systemic therapy using studies of breast cancer or EGFR-positive lung adenocarcinoma as a template. Studies already explored treatment including EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and afatinib, and also trastuzumab and its conjugation like HER2-targeted antibody-drug conjugate trastuzumab emtansine (T-DM1) and conjugate trastuzumab deruxtecan (T-DXd). Also, he researches explored combination therapy with chemotherapy and TKIs or monoclonal antibodies. This review describes commonly used therapies for HER2-positive/HER2-overexpression patients and general relationship between genotypes of HER2, drug selection and final prognosis in order to provide suggestions for future diagnosis and treatment.
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Affiliation(s)
- Ranpu Wu
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Southeast University of Medicine, Nanjing, China
| | - Bingxiao Yuan
- Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing Medical University, Nanjing, China
| | - Chuling Li
- Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing Medical University, Nanjing, China
| | - Zimu Wang
- Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Yong Song
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Southeast University of Medicine, Nanjing, China.,Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing Medical University, Nanjing, China
| | - Hongbing Liu
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Southeast University of Medicine, Nanjing, China.,Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing Medical University, Nanjing, China
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Kang H, Jeong S, Yang JK, Jo A, Lee H, Heo EH, Jeong DH, Jun BH, Chang H, Lee YS. Template-Assisted Plasmonic Nanogap Shells for Highly Enhanced Detection of Cancer Biomarkers. Int J Mol Sci 2021; 22:ijms22041752. [PMID: 33578653 PMCID: PMC7916425 DOI: 10.3390/ijms22041752] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/04/2021] [Accepted: 02/06/2021] [Indexed: 01/24/2023] Open
Abstract
We present a template-assisted method for synthesizing nanogap shell structures for biomolecular detections based on surface-enhanced Raman scattering. The interior nanogap-containing a silver shell structure, referred to as a silver nanogap shell (Ag NGS), was fabricated on silver nanoparticles (Ag NPs)-coated silica, by adsorbing small aromatic thiol molecules on the Ag NPs. The Ag NGSs showed a high enhancement factor and good signal uniformity, using 785-nm excitation. We performed in vitro immunoassays using a prostate-specific antigen as a model cancer biomarker with a detection limit of 2 pg/mL. To demonstrate the versatility of Ag NGS nanoprobes, extracellular duplex surface-enhanced Raman scattering (SERS) imaging was also performed to evaluate the co-expression of cancer biomarkers, human epidermal growth factor-2 (HER2) and epidermal growth factor receptor (EGFR), in a non-small cell lung cancer cell line (H522). Developing highly sensitive Ag NGS nanoprobes that enable multiplex biomolecular detection and imaging can open up new possibilities for point-of-care diagnostics and provide appropriate treatment options and prognosis.
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Affiliation(s)
- Homan Kang
- Interdisciplinary Program in Nano-Science and Technology, Seoul National University, Seoul 08826, Korea; (H.K.); (D.H.J.)
| | - Sinyoung Jeong
- Department of Chemistry Education, Seoul National University, Seoul 08826, Korea;
| | - Jin-Kyoung Yang
- School of Chemical & Biological Engineering, Seoul National University, Seoul 08826, Korea; (J.-K.Y.); (H.L.)
| | - Ahla Jo
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Korea;
| | - Hyunmi Lee
- School of Chemical & Biological Engineering, Seoul National University, Seoul 08826, Korea; (J.-K.Y.); (H.L.)
| | - Eun Hae Heo
- Division of Science Education, Kangwon National University, Chuncheon 24341, Korea;
| | - Dae Hong Jeong
- Interdisciplinary Program in Nano-Science and Technology, Seoul National University, Seoul 08826, Korea; (H.K.); (D.H.J.)
- Department of Chemistry Education, Seoul National University, Seoul 08826, Korea;
| | - Bong-Hyun Jun
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Korea;
- Correspondence: (B.-H.J.); (H.C.); (Y.-S.L.)
| | - Hyejin Chang
- Division of Science Education, Kangwon National University, Chuncheon 24341, Korea;
- Correspondence: (B.-H.J.); (H.C.); (Y.-S.L.)
| | - Yoon-Sik Lee
- School of Chemical & Biological Engineering, Seoul National University, Seoul 08826, Korea; (J.-K.Y.); (H.L.)
- Correspondence: (B.-H.J.); (H.C.); (Y.-S.L.)
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Abstract
Lung cancer is the leading cause of cancer mortality. It is classified into different histologic subtypes, including adenocarcinoma, squamous carcinoma, and large cell carcinoma (commonly referred as non-small cell lung cancer) and small cell lung cancer. Comprehensive molecular characterization of lung cancer has expanded our understanding of the cellular origins and molecular pathways affected in each of these subtypes. Many of these genetic alterations represent potential therapeutic targets for which drugs are constantly under development. This article discusses the molecular characteristics of the main lung cancer subtypes and discusses the current guidelines and novel targeted therapies, including checkpoint immunotherapy.
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Affiliation(s)
- Roberto Ruiz-Cordero
- Department of Pathology, University of California San Francisco, 1825 4th Street Room L2181A, San Francisco, CA 94158, USA.
| | - Walter Patrick Devine
- Department of Pathology, University of California San Francisco, 1600 Divisadero Street Room B-620, San Francisco, CA 94115, USA
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14
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Interactions between anti-EGFR therapies and cytotoxic chemotherapy in oesophageal squamous cell carcinoma: why clinical trials might have failed and how they could succeed. Cancer Chemother Pharmacol 2020; 87:361-377. [PMID: 33169187 PMCID: PMC7889538 DOI: 10.1007/s00280-020-04187-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 10/19/2020] [Indexed: 11/11/2022]
Abstract
Purpose Oesophageal squamous cell carcinoma (ESCC) has a poor prognosis. Advanced tumours are treated with fluoropyrimidine/platinum chemotherapy followed by irinotecan or taxane monotherapy, but resistance is common and new treatments are needed. Approximately 20% of ESCCs carry copy number gain (CNG) of the epidermal growth factor receptor (EGFR) gene. Previous trials show that while anti-EGFR monotherapy benefits biomarker-selected patients with EGFR CNG and/or high EGFR expression, combining anti-EGFR therapies with platinum fluoropyrimidine chemotherapies is not effective, and uncertainty remains regarding the optimal cytotoxic chemotherapy partner for anti-EGFR therapies in ESCC. Methods The effects of EGFR CNG on fluoropyrimidine/platinum chemotherapy sensitivity in a cohort of gastroesophageal cancer patients (n = 302) was evaluated. Drug combination studies using the EGFR inhibitor gefitinib with cytotoxic chemotherapies, docetaxel, cisplatin, oxaliplatin and irinotecan, on cell proliferation and cell death of EGFR CNG ESCC cell lines were assessed. Results EGFR CNG in gastroesophageal cancer patients was associated with improved overall survival following fluoropyrimidine/platinum chemotherapy. However, co-administration of gefitinib and oxaliplatin or cisplatin was frequently antagonistic in cell-based assays in EGFR CNG ESCC, whereas the combination of gefitinib with docetaxel or irinotecan was more efficacious. Co-administration of gefitinib/docetaxel and sequential administration of docetaxel before gefitinib showed synergy, but docetaxel given after gefitinib was antagonistic. Conclusion Gefitinib/platinum co-administration demonstrated antagonism suggesting a possible explanation for the lack of benefit from addition of anti-EGFR therapies to fluoropyrimidine/platinum chemotherapy in trials. Gefitinib/docetaxel co-administration demonstrated synergy suggesting taxanes could be the most effective cytotoxic partner for anti-EGFR therapies in EGFR CNG-positive ESCC, but careful consideration of drug scheduling is required.
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15
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Zhao J, Xia Y. Targeting HER2 Alterations in Non–Small-Cell Lung Cancer: A Comprehensive Review. JCO Precis Oncol 2020; 4:411-425. [PMID: 35050738 DOI: 10.1200/po.19.00333] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
PURPOSE HER2 is a critical gene that drives various solid tumors in addition to those of breast cancer. For example, HER2 plays a role in non–small-cell lung cancer (NSCLC). Overexpression, amplification, and point mutations in HER2 have been described in patients with NSCLC; however, the potential roles of these alterations remain unclear. METHODS We summarize the evidence regarding the distinct impacts of different HER2 aberrations on antitumor agents. Also, we update the therapeutic efficacy of HER2-targeted agents, including anti-HER2 antibodies, antibody-drug conjugates, and small-molecule tyrosine kinase inhibitors, tested in HER2-aberrant NSCLC. RESULTS Although these drugs are not yet standard treatments, certain patients may benefit from these therapies. In this review, we aim to provide an improved understanding of HER2 aberrations in NSCLC, including NSCLC biology and the impacts of each aberration on prognosis and standard treatment. We also highlight the potential of novel anti-HER2 therapies approved by regulatory bodies and those in clinical development. CONCLUSION Compared with HER2 amplification or overexpression, HER2 mutations, especially HER2 exon 20 mutations, are emerging as the most clear targetable driver for HER2-directed therapies in lung cancer. De novo and inducible HER2 pathway activation need to be differentially managed. Further investigations with new strategies are needed.
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Affiliation(s)
- Jing Zhao
- Department of Medical Oncology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yang Xia
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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16
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Yamaoka T, Tsurutani J, Sagara H, Ohmori T. HER2-D16 oncogenic driver mutation confers osimertinib resistance in EGFR mutation-positive non-small cell lung cancer. Transl Lung Cancer Res 2020; 9:2178-2183. [PMID: 33209639 PMCID: PMC7653124 DOI: 10.21037/tlcr-20-578] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Toshimitsu Yamaoka
- Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan.,Division of Allergology and Respiratory Medicine, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Junji Tsurutani
- Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan
| | - Hironori Sagara
- Division of Allergology and Respiratory Medicine, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Tohru Ohmori
- Division of Allergology and Respiratory Medicine, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
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Rybchenko VS, Balabashin DS, Panina AA, Solopova ON, Yakimov SA, Aliev TK, Dolgikh DA, Kirpichnikov MP. Production of the Extracellular Part of the ErbB2 Receptor for the Study of Immunobiologicals. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2020. [DOI: 10.1134/s106816202003019x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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18
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Velazquez AI, McCoach CE. Tumor evolution in epidermal growth factor receptor mutated non-small cell lung cancer. J Thorac Dis 2020; 12:2896-2909. [PMID: 32642202 PMCID: PMC7330358 DOI: 10.21037/jtd.2019.08.31] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 07/31/2019] [Indexed: 12/12/2022]
Abstract
As the incidence of cancer increases worldwide there is an unmet need to understand cancer evolution to improve patient outcomes. Our growing knowledge of cancer cells' clonal expansion, heterogeneity, adaptation, and relationships within the tumor immune compartment and with the tumor microenvironment has made clear that cancer is a disease that benefits from heterogeneity and evolution. This review outlines recent knowledge of non-small cell lung cancer (NSCLC) pathogenesis and tumor progression from an evolutionary standpoint, focused on the role of oncogenic driver mutations as epidermal growth factor receptor (EGFR). Understanding lung cancer evolution during tumor development, growth, and under treatment pressures is crucial to improve therapeutic interventions and patient outcomes.
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Affiliation(s)
- Ana I. Velazquez
- Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, CA, USA
| | - Caroline E. McCoach
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
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19
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The force of HER2 - A druggable target in NSCLC? Cancer Treat Rev 2020; 86:101996. [PMID: 32135383 DOI: 10.1016/j.ctrv.2020.101996] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/20/2020] [Accepted: 02/25/2020] [Indexed: 01/26/2023]
Abstract
Since several years targeted therapy has been part of treatment in NSCLC in subsets of patients with specific genetic alterations. One of these alterations involves HER2, a member of the ERBB family of tyrosine kinase receptors. Despite that HER2 alterations in NSCLC have been studied for years, there is still no consensus about subgroup definitions. In this review HER2 alterations in NSCLC are discussed, including diagnostic challenges and treatment strategies. Three principal mechanisms of HER2 alterations can be identified: HER2 protein overexpression, HER2 gene amplification and HER2 gene mutations. There are several methods for the detection of HER2 "positivity" in NSCLC, but no gold standard has been established. Laboratory methods for assessment of HER2 positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression and fluorescent in situ hybridization (FISH) and next generation sequencing (NGS) for genetic alterations. Many trials testing HER2 targeted therapy in HER2 altered NSCLC has not lead to a renewed standard of care for this group of patients. Therefore, today the (re)search on how to analyse, define and treat HER2 alterations in NSCLC continues. Still there is no consensus about HER2 subgroup definitions and results of the many trials studying possible treatment strategies are inconclusive. Future research should focus on the most important missing link, whether all HER2 alterations are relevant oncogenic drivers and whether it should be considered as a therapeutic target in NSCLC.
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20
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Lim SB, Lim CT, Lim WT. Single-Cell Analysis of Circulating Tumor Cells: Why Heterogeneity Matters. Cancers (Basel) 2019; 11:cancers11101595. [PMID: 31635038 PMCID: PMC6826423 DOI: 10.3390/cancers11101595] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/15/2019] [Accepted: 10/16/2019] [Indexed: 12/31/2022] Open
Abstract
Unlike bulk-cell analysis, single-cell approaches have the advantage of assessing cellular heterogeneity that governs key aspects of tumor biology. Yet, their applications to circulating tumor cells (CTCs) are relatively limited, due mainly to the technical challenges resulting from extreme rarity of CTCs. Nevertheless, recent advances in microfluidics and immunoaffinity enrichment technologies along with sequencing platforms have fueled studies aiming to enrich, isolate, and sequence whole genomes of CTCs with high fidelity across various malignancies. Here, we review recent single-cell CTC (scCTC) sequencing efforts, and the integrated workflows, that have successfully characterized patient-derived CTCs. We examine how these studies uncover DNA alterations occurring at multiple molecular levels ranging from point mutations to chromosomal rearrangements from a single CTC, and discuss their cellular heterogeneity and clinical consequences. Finally, we highlight emerging strategies to address key challenges currently limiting the translation of these findings to clinical practice.
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Affiliation(s)
- Su Bin Lim
- NUS Graduate School for Integrative Sciences & Engineering, National University of Singapore, Singapore 117456, Singapore.
- Department of Biomedical Engineering, National University of Singapore, Singapore 117583, Singapore.
| | - Chwee Teck Lim
- NUS Graduate School for Integrative Sciences & Engineering, National University of Singapore, Singapore 117456, Singapore.
- Department of Biomedical Engineering, National University of Singapore, Singapore 117583, Singapore.
- Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore.
- Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore 117599, Singapore.
| | - Wan-Teck Lim
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore.
- Office of Academic and Clinical Development, Duke-NUS Medical School, Singapore 169857, Singapore.
- IMCB NCC MPI Singapore Oncogenome Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore.
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Wang K, Yu X, Jiang H, Huang J, Wang H, Jiang H, Wei S, Liu L. Genome-wide expression profiling-based copy number variations and colorectal cancer risk in Chinese. Mol Carcinog 2019; 58:1324-1333. [PMID: 31001878 DOI: 10.1002/mc.23015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 03/30/2019] [Indexed: 12/30/2022]
Abstract
Genetic factors play important roles in colorectal carcinogenesis. This study was aimed to evaluate the effects of gene expression-related copy number variations (CNVs) on the risk of colorectal cancer in Chinese. Expression Quantitative Trait Locus (eQTL) mapping was conducted to explore the most regulatable gene expressions by CNVs among the whole genome based on publicly available data. Then a case-control study was performed to evaluate the associations between copy numbers of the most regulatable genes and colorectal cancer. The influence of the target CNVs on the expression of corresponding gene and protein was verified in colorectal tissue, and the biological effects of these CNVs on cell-cycle arrest and apoptosis of colon cancer cell lines were further detected. The eQTL revealed the most significant association between CNV of HM3_CNP_342 and gene expressions of human leukocyte antigen (HLA)-DQA1 and HLA-DQB1 among the whole genome. The later case-control study found that amplified HLA-DQB1 was inversely associated with colorectal cancer risk (odds ratio = 0.73; 95% confidence interval: 0.58-0.93), especially among those with a family history of cancer. The positive association between amplified HLA-DQB1 and upregulation of gene and protein was validated in colorectal tissue. In addition, overexpression of HLA-DQB1 in dendritic cells promoted cell-cycle arrest and apoptosis of cocultured SW480 and HCT116 cell lines, and vice versa. Our study suggests that the amplified copy number of HLA-DQB1 is associated with lower risk of colorectal cancer and able to induce the apoptosis of colon cancer cells, which implies the potential of HLA class II in cancer predisposition and immunotherapy.
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Affiliation(s)
- Ke Wang
- Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Medical College, Hubei University of Arts and Science, Xiangyang, Hubei, China
| | - Xingchen Yu
- Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hongwei Jiang
- Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jiao Huang
- Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huanzhuo Wang
- Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hongyu Jiang
- Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Sheng Wei
- Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Li Liu
- Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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22
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Ogoshi Y, Shien K, Yoshioka T, Torigoe H, Sato H, Sakaguchi M, Tomida S, Namba K, Kurihara E, Takahashi Y, Suzawa K, Yamamoto H, Soh J, Toyooka S. Anti-tumor effect of neratinib against lung cancer cells harboring HER2 oncogene alterations. Oncol Lett 2019; 17:2729-2736. [PMID: 30854046 PMCID: PMC6365915 DOI: 10.3892/ol.2019.9908] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 12/31/2018] [Indexed: 11/12/2022] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) is a member of the ErbB family of receptor tyrosine kinases. Numerous studies have reported the amplification and overexpression of HER2 in several types of cancer, including non-small cell lung cancer (NSCLC). However, the benefits of HER2-targeted therapy have not been fully established. In the present study, the anti-tumor effect of neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), against NSCLC cells harboring HER2 alterations was investigated. The sensitivity of normal bronchial epithelial cells (BEAS-2B) ectopically overexpressing wild-type or mutant HER2 to neratinib was assessed. Furthermore, the anti-tumor activity of neratinib in several NSCLC cell lines harboring HER2 alterations was determined in vitro and in vivo, and the association between their genetic alterations and sensitivity to neratinib treatment was investigated. BEAS-2B cells ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, G660D and S310F) exhibited constitutive autophosphorylation of HER2, as determined by western blotting. While these BEAS-2B cells were sensitive to neratinib, they were insensitive to erlotinib, a first-generation epidermal growth factor receptor-TKI. Neratinib also exerted anti-proliferative effects on HER2-altered (H2170, Calu-3 and H1781) NSCLC cell lines. Neratinib was also demonstrated to exert strong tumor growth inhibitory activity in mouse xenograft models using HER2-altered lung cancer cells. The results of the present study strongly suggest that neratinib has potential as a promising therapeutic option for the treatment of HER2-altered NSCLC.
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Affiliation(s)
- Yusuke Ogoshi
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Kazuhiko Shien
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Takahiro Yoshioka
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Hidejiro Torigoe
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Hiroki Sato
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Masakiyo Sakaguchi
- Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Shuta Tomida
- Department of Biobank, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Kei Namba
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Eisuke Kurihara
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Yuta Takahashi
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Ken Suzawa
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Hiromasa Yamamoto
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Junichi Soh
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Shinichi Toyooka
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
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Huang K, Liu D. Suppression of c-MET overcomes erlotinib resistance in tongue cancer cells. Onco Targets Ther 2018; 11:5499-5508. [PMID: 30233210 PMCID: PMC6134955 DOI: 10.2147/ott.s167936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background Erlotinib is a commonly used molecular-targeted drug for the treatment of tongue cancer. However, the development of acquired resistance to erlotinib hampers its therapeutic use. Materials and methods To analyze the erlotinib resistance, long-term and short term survival assay were used to compare the resistance between parental and resistant tongue cancer cells. Flow cytometry, Hochest staining and western blot were used to analyze the apoptosis among the cells. Moreover, Transwell and wound healing assay were used to compare the invasion ability of the cells. To deeply explore the drug resistance in vivo, orthotopic tumor studies were applied. Finally, to explain the mechanism of c-met in erlotinib resistance, shRNA against c-met was used to down-regulate the expression of c-met. And SU11274 also used in orthotopic model. Results We established erlotinib-resistant human tongue cancer cell line by chronic exposure of TCA-8113 cells to increasing concentrations of erlotinib and determined the role of c-MET and EGFR in the development of acquired resistance. We found a significant increase in the phosphorylation of c-MET and an obvious decrease of the phosphorylation of EGFR in erlotinib-resistant cells. Our results also revealed that inhibition of c-MET alone with SU11274 exerted an inhibitory effect on the proliferation of erlotinib-resistant cells in the short term; however, it failed to sustain the inhibitory effect in the long term. Simultaneous inhibition of c-MET and EGFR significantly inhibited the proliferation of erlotinib-resistant cells in both a short and long period. Furthermore, we explored the underlying mechanism and found that treatment of erlotinib-resistant cells with SU11274 or shRNA against c-MET induced the phosphorylation of EGFR. Moreover, our results demonstrated that simultaneous inhibition of c-MET and EGFR significantly inhibited the migration and invasion of erlotinib-resistant cells. Conclusion Taken together, our results suggested that c-MET is involved in acquired drug resistance to erlotinib and that cotargeting of EGFR and c-MET could overcome acquired resistance to erlotinib and inhibit the invasion and metastasis of erlotinib-resistant cells.
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Affiliation(s)
- Keqiang Huang
- Department of Orthodontics, School of Stomatology, Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan 250012, China,
| | - Dongxu Liu
- Department of Orthodontics, School of Stomatology, Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan 250012, China,
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Concordance analysis between HER2 immunohistochemistry and in situ hybridization in non-small cell lung cancer. Int J Biol Markers 2018; 33:49-54. [PMID: 28478639 DOI: 10.5301/ijbm.5000271] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE This study aimed to elucidate the concordance between human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) and in situ hybridization (ISH) and the diagnostic accuracy of HER2 IHC in non-small cell lung cancer (NSCLC) through a meta-analysis and diagnostic test accuracy review. METHODS Seven eligible studies and 1,217 patients with NSCLC were included in the review. The concordance between HER2 IHC and ISH was analyzed. To confirm the diagnostic accuracy of HER2 IHC, the sensitivity and specificity were analyzed and the area under the curve (AUC) in the summary receiver operating characteristic (SROC) curve was calculated. RESULTS The concordance rate between HER2 IHC and ISH was 0.795 (95% confidence interval [CI] 0.534-0.929). In the HER2 IHC-negative (score 0/1+) subgroup, the concordance rate was 0.975 (95% CI 0.854-0.996). The concordance rates of the HER2 IHC score 2+ and 3+ subgroups were 0.091 (95% CI 0.039-0.197) and 0.665 (95% CI 0.446-0.830), respectively. In diagnostic test accuracy review, the pooled sensitivity and specificity were 0.67 (95% CI 0.54-0.78) and 0.89 (95% CI 0.87-0.91), respectively. The AUC in the SROC curve was 0.891 and the diagnostic odds ratio was 16.99 (95% CI 5.08-56.76). CONCLUSIONS HER2 IHC was largely in agreement with ISH in cases of HER2 IHC score 0/1+. Because the concordance rates of HER2 IHC score 2/3+ cases were lower than that of HER2 IHC score 0/1+ cases, further studies for detailed analysis criteria for HER2 IHC score 2+ or 3+ are required.
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25
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Li J, Liu X, Yuan C. Treatment response to osimertinib in a patient with leptomeningeal metastasis from lung adenocarcinoma following failure of gefitinib and erlotinib: A case report. Mol Clin Oncol 2018; 9:321-324. [PMID: 30112177 DOI: 10.3892/mco.2018.1666] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 06/06/2018] [Indexed: 12/12/2022] Open
Abstract
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective in the treatment of advanced non-small-cell lung cancer (NSCLC) with leptomeningeal metastases (LM); however, a proportion of the patients with resistant tumors do not benefit from EGFR-TKI treatment. In the present study the case of a female patient with advanced lung adenocarcinoma harboring the EGFR L858R mutation (encoded in exon 21) who developed intracranial metastases following treatment with erlotinib after gefitinib failure is reported. The patient achieved a partial response (PR) after four cycles of chemotherapy with pemetrexed/cisplatin. However, after 4 months, LM were detected. The patient was treated with osimertinib, a third-generation EGFR-TKI, but the LM continued to progress and the patient eventually succumbed to the disease (overall survival, 6 months). Therefore, LM in patients without the EGFR T790M mutation (encoded in exon 20) appear to be resistant to treatment with the third-generation TKI osimertinib, which may be associated with human epidermal growth factor receptor 2 amplification. Further clinical trials are required to confirm our results.
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Affiliation(s)
- Junjun Li
- Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Xiaomei Liu
- Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Caijun Yuan
- Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
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26
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Guo XF, Li SS, Zhu XF, Dou QH, Liu D. Lapatinib in combination with paclitaxel plays synergistic antitumor effects on esophageal squamous cancer. Cancer Chemother Pharmacol 2018; 82:383-394. [PMID: 29909520 DOI: 10.1007/s00280-018-3627-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 06/13/2018] [Indexed: 12/29/2022]
Abstract
PURPOSE Paclitaxel-based chemoradiotherapy was proven to be efficacious in treating patients with advanced esophageal cancer. However, the toxicity and the development of resistance limited its anticancer efficiency. The present study was to evaluate the antitumor effects of lapatinib, a dual tyrosine inhibitor of both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), combined with paclitaxel on the esophageal squamous cancer. METHODS MTT assays were used to evaluate the effects of the combination of lapatinib and paclitaxel on the growth of esophageal squamous cancer cell lines (KYSE150, KYSE450, KYSE510 and TE-7). The activity of the combination of two agents on cell invasion, migration and apoptosis was measured by wound healing assay, transwell assay and Annexin V-FITC/PI stain assay. Western blot assay was used to analyze the effects of the two agents on the EGFR/HER2 signaling. The in vivo efficacy was evaluated in KYSE450 xenograft nude mouse model. RESULTS The combination of lapatinib and paclitaxel was highly synergistic in inhibiting cell growth with a combination index of < 1, and suppressed significantly the invasion and migration capability of esophageal squamous cancer cells. Esophageal squamous cancer cells displayed increased rates of apoptosis after treatment with lapatinib plus paclitaxel. The phosphorylated EGFR and HER2 as well as the activation of downstream molecules MAPKs and AKT significantly decreased when exposed to lapatinib and paclitaxel. In vivo studies showed that the combination of two agents had greater antitumor efficacy than either agent alone. CONCLUSIONS The combination of lapatinib with paclitaxel showed synergistic antitumor activity, suggesting their potential in treating patients with esophageal squamous cancer.
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Affiliation(s)
- Xiao-Fang Guo
- Department of Microbiology, School of Basic Medical Sciences, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, People's Republic of China.
| | - Sai-Sai Li
- Department of Microbiology, School of Basic Medical Sciences, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, People's Republic of China
| | - Xiao-Fei Zhu
- Department of Clinical Immunology, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, People's Republic of China.,Henan Collaborative Innovation center of Molecular Diagnosis and Laboratory Medicine, Xinxiang, People's Republic of China
| | - Qiao-Hua Dou
- Department of Microbiology, School of Basic Medical Sciences, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, People's Republic of China
| | - Duan Liu
- Department of Gynecology and Obstetrics, Third Affiliated Hospital, Zhengzhou University, Zhengzhou, People's Republic of China
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27
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Torigoe H, Shien K, Takeda T, Yoshioka T, Namba K, Sato H, Suzawa K, Yamamoto H, Soh J, Sakaguchi M, Tomida S, Tsukuda K, Miyoshi S, Toyooka S. Therapeutic strategies for afatinib-resistant lung cancer harboring HER2 alterations. Cancer Sci 2018. [PMID: 29532558 PMCID: PMC5980184 DOI: 10.1111/cas.13571] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) plays an important role in the pathogenesis of various cancers. HER2 alterations have been suggested to be a therapeutic target in non-small-cell lung cancer (NSCLC), just as in breast and gastric cancers. We previously reported that the pan-HER inhibitor afatinib could be a useful therapeutic agent as HER2-targeted therapy for patients with NSCLC harboring HER2 alterations. However, acquired resistance to afatinib was observed in the clinical setting, similar to the case for other HER inhibitors. Thus, elucidation of the mechanisms underlying the development of acquired drug resistance and exploring means to overcome acquired drug resistance are important issues in the treatment of NSCLC. In this study, we experimentally established afatinib-resistant cell lines from NSCLC cell lines harboring HER2 alterations, and investigated the mechanisms underlying the acquisition of drug resistance. The established cell lines showed several unique afatinib-resistance mechanisms, including MET amplification, loss of HER2 amplification and gene expression, epithelial-to-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. The afatinib-resistant cell lines showing MET amplification were sensitive to the combination of afatinib plus crizotinib (a MET inhibitor), both in vitro and in vivo. The resistant cell lines which showed EMT or had acquired CSC-like features remained sensitive to docetaxel, like the parental cells. These findings may provide clues to countering the resistance to afatinib in NSCLC patients with HER2 alterations.
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Affiliation(s)
- Hidejiro Torigoe
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kazuhiko Shien
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Tatsuaki Takeda
- Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Takahiro Yoshioka
- Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kei Namba
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiroki Sato
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Ken Suzawa
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiromasa Yamamoto
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Junichi Soh
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Masakiyo Sakaguchi
- Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shuta Tomida
- Biobank, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kazunori Tsukuda
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shinichiro Miyoshi
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shinichi Toyooka
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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28
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Cappuzzo F, Landi L. HER2 Deregulation in Lung Cancer: Right Time to Adopt an Orphan? Clin Cancer Res 2018; 24:2470-2472. [DOI: 10.1158/1078-0432.ccr-18-0198] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 02/13/2018] [Accepted: 02/27/2018] [Indexed: 11/16/2022]
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29
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Liu Q, Yu S, Zhao W, Qin S, Chu Q, Wu K. EGFR-TKIs resistance via EGFR-independent signaling pathways. Mol Cancer 2018; 17:53. [PMID: 29455669 PMCID: PMC5817859 DOI: 10.1186/s12943-018-0793-1] [Citation(s) in RCA: 252] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 02/01/2018] [Indexed: 01/29/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs)-treatments bring significant benefit for patients harboring epidermal growth factor receptor (EGFR) mutations, especially for those with lung cancer. Unfortunately, the majority of these patients ultimately develop to the acquired resistance after a period of treatment. Two central mechanisms are involved in the resistant process: EGFR secondary mutations and bypass signaling activations. In an EGFR-dependent manner, acquired mutations, such as T790 M, interferes the interaction between TKIs and the kinase domain of EGFR. While in an EGFR-independent manner, dysregulation of other receptor tyrosine kinases (RTKs) or abnormal activation of downstream compounds both have compensatory functions against the inhibition of EGFR through triggering phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) signaling axes. Nowadays, many clinical trials aiming to overcome and prevent TKIs resistance in various cancers are ongoing or completed. EGFR-TKIs in accompany with the targeted agents for resistance-related factors afford a promising first-line strategy to further clinical application.
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Affiliation(s)
- Qian Liu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shengnan Yu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Weiheng Zhao
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shuang Qin
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Qian Chu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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30
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Abstract
We report here on the state of our knowledge of the target - namely, the epidermal growth factor (EGF) and its receptor - and the challenges related to the methods of determination of the epidermal growth factor receptor (EGFR) and associated molecular pathways. A critical review of the anti-EGFR therapeutic strategies is also outlined. The chimeric anti-EGFR monoclonal antibody cetuximab has been approved for EGFR-expressing colorectal tumors in patients who progress after irinotecan-based chemotherapy in combination with irinotecan and in squamous cell head and neck carcinomas for patients with locally advanced disease in combination with radiation therapy or after failure of platinum-based chemotherapy in recurrent or metastatic disease (FDA). Cetuximab has the potential to provide an improvement of clinical outcome also in other indications and tumor types, particularly when used as first-line therapy combined with standard chemotherapy for metastatic disease or in the adjuvant setting. Possible strategies to improve the effectiveness of anti-EGFR agents are suggested and include (i) the use of predictive tools capable of making a more rational selection of patients; (ii) the development of standardized predictive biomarkers as surrogates for early monitoring of drug efficacy; and (iii) adequate study design, statistical analysis and proper end points of efficacy to be applied in future prospective trials.
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Affiliation(s)
- M.R. D'Andrea
- Division of Medical Oncology, Azienda Complesso Ospedaliero S. Filippo Neri, Rome - Italy
| | - G. Gasparini
- Division of Medical Oncology, Azienda Complesso Ospedaliero S. Filippo Neri, Rome - Italy
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31
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Cappuzzo F, Toschi L, Finocchiaro G, Ligorio C, Santoro A. Surrogate Predictive Biomarkers for Response to Anti-EGFR Agents: State of the Art and Challenges. Int J Biol Markers 2018; 22:10-23. [DOI: 10.1177/17246008070221s403] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The epidermal growth factor receptor (EGFR) plays a key role in cancer development and progression in several human malignancies including non-small cell lung cancer (NSCLC). Several strategies aimed at inhibiting the EGFR have been investigated in the last years, including the use of small tyrosine kinase inhibitors (TKIs) directed against the intracellular domain of the receptor and monoclonal antibodies targeting its extracellular portion. Subgroups of patients who are more likely to respond to TKIs have been identified based on both clincal and biological features. Never-smoking history has emerged as the most relevant clinical characteristic predictive of response to TKIs in NSCLC, while presence of drug-sensitive EGFR mutations and EGFR gene gain represent critical biological variables associated with an improved outcome for patients exposed to these agents. Recent studies have highlighted the existence of biological factors involved in intrinsic and acquired resistance to TKIs, including k-ras, HER-2 and EGFR exon 20 mutations. Increasing knowledge of EGFR biology and drug-receptor interactions will allow to identify individuals who are likely to derive a clinical benefit from the proposed targeted therapy, sparing refractory patients expensive and potentially toxic treatment.
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Affiliation(s)
- F. Cappuzzo
- Department of Oncology-Hematology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan - Italy
| | - L. Toschi
- Department of Oncology-Hematology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan - Italy
| | - G. Finocchiaro
- Department of Oncology-Hematology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan - Italy
| | - C. Ligorio
- Department of Oncology-Hematology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan - Italy
| | - A. Santoro
- Department of Oncology-Hematology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan - Italy
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32
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Xu J, Wang J, Zhang S. Mechanisms of resistance to irreversible epidermal growth factor receptor tyrosine kinase inhibitors and therapeutic strategies in non-small cell lung cancer. Oncotarget 2017; 8:90557-90578. [PMID: 29163853 PMCID: PMC5685774 DOI: 10.18632/oncotarget.21164] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 08/28/2017] [Indexed: 11/25/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) T790M mutation is the most frequent mechanism which accounts for about 60% of acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients harboring EGFR activating mutations. Irreversible EGFR-TKIs which include the second-generation and third-generation EGFR-TKIs are developed to overcome T790M mediated resistance. The second-generation EGFR-TKIs inhibit the wide type (WT) EGFR combined with dose-limiting toxicity which limits its application in clinics, while the development of third-generation EGFR-TKIs brings inspiring efficacy either in vitro or in vivo. The acquired resistance, however, will also occur and limit their response. Understanding the mechanisms of resistance to irreversible EGFR-TKIs plays an important role in the choice of subsequent treatment. In this review, we show the currently known mechanisms of resistance which can be summarized as EGFR dependent and independent mechanisms and potential therapeutic strategies to irreversible EGFR-TKIs.
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Affiliation(s)
- Jing Xu
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Jinghui Wang
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Shucai Zhang
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, China
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33
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Kanwal M, Ding XJ, Ma ZH, Li LW, Wang P, Chen Y, Huang YC, Cao Y. Characterization of germline mutations in familial lung cancer from the Chinese population. Gene 2017; 641:94-104. [PMID: 29054765 DOI: 10.1016/j.gene.2017.10.020] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 10/07/2017] [Indexed: 11/18/2022]
Abstract
Compared with numerous studies of somatic mutations using sporadic lung cancer, the research into germline mutations using familial lung cancer (FLC) is limited. In the present study, we used FLC samples obtained from the Chinese population in highly air-polluted regions to screen for novel germline mutations in lung cancer. Through a whole genome sequencing (WGS) analysis of the nine subjects (four lung cancer patients and five normal family members of FLC), we obtained a whole genome dataset of DNA alterations in FLC samples. A total of 1218 genes were identified with mutations of multiple types. Subsequently, the top 12 highly mutated genes were selected for validation by polymerase chain reaction and DNA sequencing in an expanded sample set including FLC, sporadic lung cancer, and healthy population. Mutations of the five genes (ARHGEF5, ANKRD20A2, ZNF595, ZNF812, MYO18B) may be potential germline mutations of lung cancer. We also analyzed specific mutations within the 12 genes and found that some specific mutations within the MUC12, FOXD4L3 and FOXD4L5 genes showed higher frequencies in the samples of FLC and/or lung cancer tissue, compared with the healthy population. Moreover, some genes with copy number variation may be potentially associated with a predisposition to lung cancer. Furthermore, non-coding DNA alterations of the WGS data in FLC were systematically analyzed and arranged. Interestingly, we found that germline mutations also occurred in many genes of non-coding RNA. This study uncovered the mutation spectrum in FLC and provided important clues for the evaluation of the genetic susceptibility to lung cancer.
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Affiliation(s)
- Madiha Kanwal
- Laboratory of Molecular and Experimental Pathology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China; Kunming College of Life Sciences, University of Chinese Academy of Sciences, Kunming, China
| | - Xiao-Jie Ding
- Laboratory of Molecular and Experimental Pathology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Zhans-Han Ma
- Computational Biology and Medical Ecology Laboratory, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Lian-Wei Li
- Computational Biology and Medical Ecology Laboratory, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Ping Wang
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, Kunming, China
| | - Ying Chen
- Department of Thoracic and Cardiovascular Surgery, The Third Affiliated Hospital of Kunming Medical University (Yunnan Tumor Hospital), Kunming, China; The International Cooperation Key Laboratory of Regional Tumor in High Altitude Area, Ministry of Education of the People's Republic of China, Kunming, China
| | - Yun-Chao Huang
- Department of Thoracic and Cardiovascular Surgery, The Third Affiliated Hospital of Kunming Medical University (Yunnan Tumor Hospital), Kunming, China; The International Cooperation Key Laboratory of Regional Tumor in High Altitude Area, Ministry of Education of the People's Republic of China, Kunming, China.
| | - Yi Cao
- Laboratory of Molecular and Experimental Pathology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
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Oh DY, Jung K, Song JY, Kim S, Shin S, Kwon YJ, Oh E, Park WY, Song SY, Choi YL. Precision medicine approaches to lung adenocarcinoma with concomitant MET and HER2 amplification. BMC Cancer 2017; 17:535. [PMID: 28806950 PMCID: PMC5557466 DOI: 10.1186/s12885-017-3525-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 08/01/2017] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Patient-derived xenograft (PDX) models are important tools in precision medicine and for the development of targeted therapies to treat cancer patients. This study aimed to evaluate our precision medicine strategy that integrates genomic profiling and preclinical drug-screening platforms, in order to personalize cancer treatments using PDX models. METHODS We performed array-comparative genomic hybridization, microarray, and targeted next-generation sequencing analyses, in order to determine the oncogenic driver mutations. PDX cells were obtained from PDXs and subsequently screened in vitro with 17 targeted agents. RESULTS PDX tumors recapitulated the histopathologic and genetic features of the patient tumors. Among the samples from lung cancer patients that were molecularly-profiled, copy number analysis identified unique focal MET amplification in one sample, 033 T, without RTK/RAS/RAF oncogene mutations. Although HER2 amplification in 033 T was not detected in the cancer panel, the selection of HER2-amplified clones was found in PDXs and PDX cells. Additionally, MET and HER2 overexpression were found in patient tumors, PDXs, and PDX cells. Crizotinib or EGFR tyrosine kinase inhibitor treatments significantly inhibited cell growth and impaired tumor sphere formation in 033 T PDX cells. CONCLUSIONS We established PDX cell models using surgical samples from lung cancer patients, and investigated their preclinical and clinical implications for personalized targeted therapy. Additionally, we suggest that MET and EGFR inhibitor-based therapy can be used to treat MET and HER2-overexpressing lung cancers, without receptor tyrosine kinase /RAS/RAF pathway alterations.
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Affiliation(s)
- Doo-Yi Oh
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea
| | - Kyungsoo Jung
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea
| | - Ji-Young Song
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea
| | - Seokhwi Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea
| | - Sang Shin
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea
| | - Yong-Jun Kwon
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea
| | - Ensel Oh
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea
| | - Woong-Yang Park
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea.,Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea
| | - Sang Yong Song
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea.,Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea
| | - Yoon-La Choi
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea. .,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea.
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35
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Lee KE, Hahm E, Bae S, Kang JS, Lee WJ. The enhanced tumor inhibitory effects of gefitinib and L-ascorbic acid combination therapy in non-small cell lung cancer cells. Oncol Lett 2017; 14:276-282. [PMID: 28693165 DOI: 10.3892/ol.2017.6109] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 03/03/2017] [Indexed: 12/28/2022] Open
Abstract
Despite documentation of successful therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with lung cancer, the response rate of patients treated with this therapy remains low. The present study investigated whether L-ascorbic acid serves an adjuvant role in vitro when combined with the EGFR tyrosine kinase inhibitor gefitinib (Iressa®) in lung cancer cell lines. A total of three human lung cancer cell lines were used. The antiproliferative effects and changes in the cell cycle and expression of intracellular signaling molecules, including extracellular signal-regulated kinases (Erk), signal transducer and activator of transcription 3 (Stat3) and protein kinase B (Akt), were measured in cells treated with gefitinib and/or L-ascorbic acid at various concentrations. When combined with gefitinib, L-ascorbic acid exhibited an additive effect on cell proliferation in all gefitinib-sensitive and gefitinib-resistant cell lines. A decrement of ~40% was observed with a low dose 0.5 mM L-ascorbic acid and gefitinib in the relatively gefitinib-resistant A549 cell line (85.6±5.4% with gefitinib alone vs. 52.7±7.3% with combination therapy; P=0.046). The downregulation of intracellular signaling cascades, including EGFR, Akt, Erk and Stat3, was also observed. L-Ascorbic acid serves an adjuvant role when administered in combination with gefitinib; however, the degree of inhibition of cell proliferation differs between lung cancer cell lines.
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Affiliation(s)
- Kyoung Eun Lee
- Division of Hematology-Oncology, Department of Internal Medicine, School of Medicine, Ewha Womans University, Seoul 07985, Republic of Korea
| | - Eunsil Hahm
- Department of Anatomy and Tumor Immunity Medical Research Center, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea
| | - Seyeon Bae
- Department of Anatomy and Tumor Immunity Medical Research Center, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea
| | - Jae Seung Kang
- Department of Anatomy and Tumor Immunity Medical Research Center, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea
| | - Wang Jae Lee
- Department of Anatomy and Tumor Immunity Medical Research Center, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea
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Scrima M, Zito Marino F, Oliveira DM, Marinaro C, La Mantia E, Rocco G, De Marco C, Malanga D, De Rosa N, Rizzuto A, Botti G, Franco R, Zoppoli P, Viglietto G. Aberrant Signaling through the HER2-ERK1/2 Pathway is Predictive of Reduced Disease-Free and Overall Survival in Early Stage Non-Small Cell Lung Cancer (NSCLC) Patients. J Cancer 2017; 8:227-239. [PMID: 28243327 PMCID: PMC5327372 DOI: 10.7150/jca.17093] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 10/17/2016] [Indexed: 12/30/2022] Open
Abstract
Background: Purpose of this study was to evaluate the contribution of the Extracellular-regulated protein kinase (ERK)-1/2 pathway to oncogenic signaling elicited by the tyrosine kinase receptor HER2 in Non-Small Cell Lung Cancer (NSCLC) and to assess the prognostic value of these oncoproteins in NSCLC patients. Methods: Immunohistochemistry was performed to determine expression and activation of HER2 and ERK1/2 (detected by phosphorylation of Y1248 and T202/Y204, respectively) using Tissue Micro Arrays (TMA) containing matched normal and neoplastic tissues from 132 NSCLC patients. Survival analysis was carried out using the Kaplan-Meier method. Univariate and multivariate analysis were used to evaluate the prognostic value of pERK1/2, pHER2 and a combination thereof with clinical-pathological parameters such as age, lymph node status (N), size (T), stage (TNM) and grade. Results: We found that HER2 was overexpressed in 33/120 (27%) and activated in 41/114 (36%) cases; ERK1/2 was activated in 44/102 (43%) cases. A direct association was found between pERK1/2 and pHER2 (23/41; p=0.038). In addition, patients positive for pERK1/2 and for both pHER2 and pERK1/2 showed significantly worse overall survival (OS) and disease-free survival (DFS) compared with negative patients. Univariate and multivariate analysis of patients' survival revealed that positivity for pHER2-pERK1/2 and for pERK1/2 alone were independent prognostic factors of poor survival in NSCLC patients. In particular, this association was significantly important for DFS in stage I+II patients. Conclusion: This study provides evidence that activated ERK1/2 and/or the combined activation of HER2 and ERK1/2 are good indicators of poor prognosis in NSCLC patients, not only in unselected patients but also in early stage disease.
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Affiliation(s)
- Marianna Scrima
- Biogem scarl, Institute of Genetic Research, Ariano Irpino (AV), Italy.; Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy
| | - Federica Zito Marino
- Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Duarte Mendes Oliveira
- Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy
| | - Cinzia Marinaro
- Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy
| | - Elvira La Mantia
- Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Gaetano Rocco
- Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Carmela De Marco
- Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy
| | - Donatella Malanga
- Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy
| | | | - Antonia Rizzuto
- Department of Medical and Surgical Sciences, University "Magna Graecia" Medical School, Catanzaro, Italy
| | - Gerardo Botti
- Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | | | - Pietro Zoppoli
- Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy
| | - Giuseppe Viglietto
- Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy
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Khan SA, Zeng Z, Shia J, Paty PB. EGFR Gene Amplification and KRAS Mutation Predict Response to Combination Targeted Therapy in Metastatic Colorectal Cancer. Pathol Oncol Res 2016; 23:673-677. [PMID: 28025786 DOI: 10.1007/s12253-016-0166-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 12/14/2016] [Indexed: 12/27/2022]
Abstract
Genetic variability in KRAS and EGFR predicts response to cetuximab in irinotecan refractory colorectal cancer. Whether these markers or others remain predictive in combination biologic therapies including bevacizumab is unknown. We identified predictive biomarkers from patients with irinotecan refractory metastatic colorectal cancer treated with cetuximab plus bevacizumab. Patients who received cetuximab plus bevacizumab for irinotecan refractory colorectal cancer in either of two Phase II trials conducted were identified. Tumor tissue was available for 33 patients. Genomic DNA was extracted and used for mutational analysis of KRAS, BRAF, and p53 genes. Fluorescence in situ hybridization was performed to assess EGFR copy number. The status of single genes and various combinations were tested for association with response. Seven of 33 patients responded to treatment. KRAS mutations were found in 14/33 cases, and 0 responded to treatment (p = 0.01). EGFR gene amplification was seen in 3/33 of tumors and in every case was associated with response to treatment (p < 0.001). TP53 and BRAF mutations were found in 18/33 and 0/33 tumors, respectively, and there were no associations with response to either gene. EGFR gene amplification and KRAS mutations are predictive markers for patients receiving combination biologic therapy of cetuximab plus bevacizumab for metastatic colorectal cancer. One marker or the other is present in the tumor of half of all patients allowing treatment response to be predicted with a high degree of certainty. The role for molecular markers in combination biologic therapy seems promising.
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Affiliation(s)
- Sajid A Khan
- Department of Surgery, Section of Surgical Oncology, Yale University School of Medicine, 310 Cedar Street, FMB 130, New Haven, CT, 06520, USA.
| | - Zhaoshi Zeng
- Colorectal Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Jinru Shia
- Colorectal Service, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Philip B Paty
- Colorectal Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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Xu J, Shen L, Zhang BC, Xu WH, Ruan SQ, Pan C, Wei QC. HER2 overexpression reverses the relative resistance of EGFR-mutant H1975 cell line to gefitinib. Oncol Lett 2016; 12:5363-5369. [PMID: 28105244 DOI: 10.3892/ol.2016.5373] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Accepted: 10/24/2016] [Indexed: 01/12/2023] Open
Abstract
Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that has been demonstrated to be clinically useful for the treatment of patients with non-small cell lung cancer (NSCLC). However, ~50% of patients do not respond to EGFR TKI treatment through the emergence of mutations, such as T790M. Therefore, it is important to determine which patients are eligible for treatment with gefitinib. As a preferred dimerization partner for EGFR, the role of EGFR 2 (HER2) in mediating sensitivity to gefitinib is poorly understood. In the present study, full-length human HER2 cDNA was introduced to the NSCLC cell lines H1975 and H1299, which have a low endogenous expression level of HER2. In addition, it was observed in the present study that the H1975 cell line harbored the L858R and T790M mutations in the EGFR kinase domain. Western blot analysis and MTT assay were used to evaluate the TKI sensitivity of HER2 expression status, and the activation of HER3 and HER2 downstream effectors. The results indicated that the sensitivity of H1975 cells to gefitinib was restored by the overexpression of HER2, which stimulated HER2-driven signaling cascades accompanied by the activation of protein kinase B. By contrast, ectopic HER2 overexpression in H1299 cells did not significantly alter the sensitivity to gefitinib treatment. In conclusion, the current study results suggested that the relatively resistance of the H1975 cell line to gefitinib could be reversed by the overexpression of HER2. Therefore, the expression of HER2 could also be considered when evaluate the patients' potential response to gefitinib, particularly in the subgroup of lung cancer patients who harbor an EGFR mutation.
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Affiliation(s)
- Jing Xu
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China; National Ministry of Education Key Laboratory of Cancer Prevention and Intervention, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Li Shen
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China; National Ministry of Education Key Laboratory of Cancer Prevention and Intervention, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Bi-Cheng Zhang
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Wen-Hong Xu
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China; National Ministry of Education Key Laboratory of Cancer Prevention and Intervention, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Shu-Qin Ruan
- Department of Oncology, Chongqing Zhongshan Hospital, Chongqing 400013, P.R. China
| | - Chi Pan
- National Ministry of Education Key Laboratory of Cancer Prevention and Intervention, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Qi-Chun Wei
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China; National Ministry of Education Key Laboratory of Cancer Prevention and Intervention, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
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Epidermal Growth Factor Receptor (EGFR) Pathway Biomarkers in the Randomized Phase III Trial of Erlotinib Versus Observation in Ovarian Cancer Patients with No Evidence of Disease Progression after First-Line Platinum-Based Chemotherapy. Target Oncol 2016; 10:583-96. [PMID: 26004768 DOI: 10.1007/s11523-015-0369-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
BACKGROUND In this work, we aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in patients with ovarian cancer who were treated within the phase III randomized European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG) 55041 study comparing erlotinib with observation in patients with no evidence of disease progression after first-line platinum-based chemotherapy. METHODS Somatic mutations in KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN were determined in 318 (38 %) and expression of EGFR, pAkt, pMAPK, E-cadherin and Vimentin, and EGFR and HER2 gene copy numbers in 218 (26 %) of a total of 835 randomized patients. Biomarker data were correlated with progression-free survival (PFS) and overall survival (OS). RESULTS Only 28 mutations were observed among KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN (in 7.5 % of patients), of which the most frequent were in KRAS and PIK3CA. EGFR mutations occurred in only three patients. When all mutations were pooled, patients with at least one mutation in KRAS, NRAS, BRAF, PIK3CA, or EGFR had longer PFS (33.1 versus 12.3 months; HR 0.57; 95 % CI 0.33 to 0.99; P = 0.042) compared to those with wild-type tumors. EGFR overexpression was detected in 93 of 218 patients (42.7 %), and 66 of 180 patients (36.7 %) had EGFR gene amplification or high levels of copy number gain. Fifty-eight of 128 patients had positive pMAPK expression (45.3 %), which was associated with inferior OS (38.9 versus 67.0 months; HR 1.81; 95 % CI 1.11 to 2.97; P = 0.016). Patients with positive EGFR fluorescence in situ hybridization (FISH) status had worse OS (46.1 months) than those with negative status (67.0 months; HR 1.56; 95 % CI 1.01 to 2.40; P = 0.044) and shorter PFS (9.6 versus 16.1 months; HR 1.57; 95 % CI 1.11 to 2.22; P = 0.010). None of the investigated biomarkers correlated with responsiveness to erlotinib. CONCLUSIONS In this phase III study, increased EGFR gene copy number was associated with worse OS and PFS in patients with ovarian cancer. It remains to be determined whether this association is purely prognostic or is also predictive.
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Liu L, Huang J, Wang K, Li L, Li Y, Yuan J, Wei S. Identification of hallmarks of lung adenocarcinoma prognosis using whole genome sequencing. Oncotarget 2016; 6:38016-28. [PMID: 26497366 PMCID: PMC4741981 DOI: 10.18632/oncotarget.5697] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 09/30/2015] [Indexed: 11/25/2022] Open
Abstract
In conjunction with clinical characteristics, prognostic biomarkers are essential for choosing optimal therapies to lower the mortality of lung adenocarcinoma. Whole genome sequencing (WGS) of 7 cancerous-noncancerous tissue pairs was performed to explore the comparative copy number variations (CNVs) associated with lung adenocarcinoma. The frequencies of top ranked CNVs were verified in an independent set of 114 patients and then the roles of target CNVs in disease prognosis were assessed in 313 patients. The WGS yielded 2604 CNVs. After frequency validation and biological function screening of top 10 CNVs, 9 mutant driver genes from 7 CNVs were further analyzed for an association with survival. Compared with the PBXIP1 amplified copy number, unamplified carriers had a 0.62-fold (95%CI = 0.43–0.91) decreased risk of death. Compared with an amplified TERT, those with an unamplified TERT had a 35% reduction (95% CI = 3%–56%) in risk of lung adenocarcinoma progression. Cases with both unamplified PBXIP1 and TERT had a median 34.32-month extension of overall survival and 34.55-month delay in disease progression when compared with both amplified CNVs. This study demonstrates that CNVs of TERT and PBXIP1 have the potential to translate into the clinic and be used to improve outcomes for patients with this fatal disease.
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Affiliation(s)
- Li Liu
- Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Jiao Huang
- Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Ke Wang
- Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Li Li
- Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Yangkai Li
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Jingsong Yuan
- Department of Radiation Oncology, Center for Radiological Research, Columbia University Medical Center, New York, NY, USA
| | - Sheng Wei
- Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
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Zhang K, Wang H. [Role of HER2 in NSCLC]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2016; 18:644-51. [PMID: 26483338 PMCID: PMC6000084 DOI: 10.3779/j.issn.1009-3419.2015.10.08] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
过去几年中, 随着分子靶向药物的引入, 非小细胞肺癌(non-small cell lung cancer, NSCLC)的药物治疗策略发生了巨大变化, 向基于组织学和分子水平的治疗手段转变。表皮生长因子受体(epidermal growth factor receptor, EGFR)突变、Kirsten鼠肉瘤(Kirsten rat sarcoma, KRAS)癌基因突变、间变淋巴瘤激酶(anaplastic lymphoma kinase, ALK)重排等的发现, 影响着NSCLC治疗的发展。最近, 对人表皮生长因子受体2(human epidermal growth factor receptor 2, HER2)研究重燃兴趣, 这一基因改变与NSCLC对不同酪氨酸激酶抑制剂(tyrosine kinase inhibitors, TKIs)的敏感性相关, 其具有可能的预测作用, HER2扩增可能是EGFR突变肿瘤对EGFR-TKIs获得性耐药的机制之一。其次, HER2突变可能阐明一条新的靶向治疗NSCLC的策略。本文将对NSCLC中HER2异常调节发挥的作用做一简要介绍。
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Affiliation(s)
- Kun Zhang
- Department of Lung Oncology, Affiliated Hospital of The PLA Military Academy of Medical Sciences, Beijing 100071, China
| | - Hong Wang
- Department of Lung Oncology, Affiliated Hospital of The PLA Military Academy of Medical Sciences, Beijing 100071, China
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42
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Holst F. Estrogen receptor alpha gene amplification in breast cancer: 25 years of debate. World J Clin Oncol 2016; 7:160-173. [PMID: 27081639 PMCID: PMC4826962 DOI: 10.5306/wjco.v7.i2.160] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 01/05/2016] [Accepted: 02/16/2016] [Indexed: 02/06/2023] Open
Abstract
Twenty-five years ago, Nembrot and colleagues reported amplification of the estrogen receptor alpha gene (ESR1) in breast cancer, initiating a broad and still ongoing scientific debate on the prevalence and clinical significance of this genetic aberration, which affects one of the most important genes in breast cancer. Since then, a multitude of studies on this topic has been published, covering a wide range of divergent results and arguments. The reported prevalence of this alteration in breast cancer ranges from 0% to 75%, suggesting that ESR1 copy number analysis is hampered by technical and interpreter issues. To date, two major issues related to ESR1 amplification remain to be conclusively addressed: (1) The extent to which abundant amounts of messenger RNA can mimic amplification in standard fluorescence in situ hybridization assays in the analysis of strongly expressed genes like ESR1, and (2) the clinical relevance of ESR1 amplification: Such relevance is strongly disputed, with data showing predictive value for response as well as for resistance of the cancer to anti-estrogen therapies, or for subsequent development of cancers in the case of precursor lesions that display amplification of ESR1. This review provides a comprehensive summary of the various views on ESR1 amplification, and highlights explanations for the contradictions and conflicting data that could inform future ESR1 research.
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Kuwano M, Sonoda K, Murakami Y, Watari K, Ono M. Overcoming drug resistance to receptor tyrosine kinase inhibitors: Learning from lung cancer. Pharmacol Ther 2016; 161:97-110. [PMID: 27000770 DOI: 10.1016/j.pharmthera.2016.03.002] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
There are various receptor tyrosine kinase (TK)-targeted drugs that are currently used in the treatment of patients with non-small cell lung cancer (NSCLC). Among them, the epidermal growth factor receptor (EGFR) TK inhibitors (TKIs) are the most extensively studied. Receptor TKIs including EGFR TKIs have shown dramatic therapeutic efficacies in malignant tumors, which harbor activating mutations in the EGFR gene. However, within 1 or 2years after treatment, patients harboring these mutations often develop resistance to TKI therapy. This review article is aimed at drawing attention to the fact that we must first understand how receptor TKI resistance is acquired to develop strategies for overcoming resistance to TKIs. Furthermore, an insight into the specific molecules or signaling pathways that mediate resistance is a key factor for understanding and overcoming acquired drug resistance. Finally, we present our views on the continuing battle against "drug resistance," and provide further guidelines and strategies on how to minimize the development of drug-resistant tumors.
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Affiliation(s)
- Michihiko Kuwano
- Cancer Translational Research Center, St. Mary's Institute of Health Sciences, St. Mary's Hospital, Kurume 830-8543, Japan; Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
| | - Kahori Sonoda
- Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yuichi Murakami
- Cancer Translational Research Center, St. Mary's Institute of Health Sciences, St. Mary's Hospital, Kurume 830-8543, Japan; Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kosuke Watari
- Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Mayumi Ono
- Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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44
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Targeting non-canonical autophagy overcomes erlotinib resistance in tongue cancer. Tumour Biol 2016; 37:9625-33. [PMID: 26797786 DOI: 10.1007/s13277-015-4689-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 12/16/2015] [Indexed: 01/11/2023] Open
Abstract
Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) frequently occurs in many human cancers and hampers their therapeutic use. A large body of evidence has demonstrated the pro-survival role of autophagy in many human cancers. However, whether autophagy is involved in the induction of erlotinib resistance in tongue squamous cell carcinoma (TSCC) remains unknown. In this report, we found that autophagy prior to or induced by erlotinib treatment plays an important role in erlotinib resistance in tongue cancer cells. Using LC3 transfection, we observed that autophagy is upregulated and further induced when treated with erlotinib. Moreover, we found that autophagy plays a cytoprotective role by MTT analysis of the cell viability in TSCCs when treated with rapamycin or hydroxychloroquine (HCQ) in combination with erlotinib. However, 3-methyladenine (3-MA) did not influence the autophagy. Then, through siRNA technology and WB, we found that erlotinib-induced autophagy is mediated by ATG5 but not Beclin1. Also, knockdown of ATG5 significantly decreased the erlotinib resistance and knockdown of Beclin1 did not affect the sensitivity to erlotinib in TSCCs. Taken together, this indicates the critical role of non-canonical autophagy in erlotinib resistance in TSCCs.
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Landi L, Cappuzzo F. Ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer. Expert Rev Clin Pharmacol 2015; 9:203-14. [DOI: 10.1586/17512433.2016.1122518] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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Suzawa K, Toyooka S, Sakaguchi M, Morita M, Yamamoto H, Tomida S, Ohtsuka T, Watanabe M, Hashida S, Maki Y, Soh J, Asano H, Tsukuda K, Miyoshi S. Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations. Cancer Sci 2015; 107:45-52. [PMID: 26545934 PMCID: PMC4724821 DOI: 10.1111/cas.12845] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 10/21/2015] [Accepted: 10/31/2015] [Indexed: 01/26/2023] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non-small-cell lung cancer (NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2-targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor (EGFR)-HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS-2B, ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2-altered NSCLC cells (H2170, Calu-3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G1 arrest and apoptotic cell death. In contrast, HER2- or EGFR-non-dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2-altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2-targeted therapy for NSCLC harboring HER2 amplification or mutations.
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Affiliation(s)
- Ken Suzawa
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shinichi Toyooka
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Department of Biobank, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Masakiyo Sakaguchi
- Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Mizuki Morita
- Department of Biobank, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Department of Biorepository Research and Networking, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiromasa Yamamoto
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shuta Tomida
- Department of Biobank, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Tomoaki Ohtsuka
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Mototsugu Watanabe
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shinsuke Hashida
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yuho Maki
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Junichi Soh
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Department of Biobank, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiroaki Asano
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kazunori Tsukuda
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shinichiro Miyoshi
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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Abstract
The therapeutic landscape of non-small-cell lung cancer (NSCLC) has dramatically changed in the last few years with the introduction of molecularly targeted agents, leading to unprecedented results in lung tumors with a paradigmatic shift from a "one size fits all" approach to an histologic and molecular-based approach. The discovery of epidermal growth factor receptor (EGFR) mutations in NSCLC in 2004 and the marked response to the EGFR tyrosine kinase inhibitor gefitinib, in a small subset of patients harboring these genetic abnormalities, stimulated the study of other kinase mutants involvement in NSCLC. The incredible story of ALK rearranged tumors, with the rapid Food and Drug Administration approval of Crizotinib after only 4 years from the discovery of EML4-ALK translocation in NSCLC, has profoundly influenced the concept of drug development in NSCLC, paving the way to a novel series of molecularly selected studies with specific inhibitors. The identification of these oncogenic drivers has dramatically changed the genetic landscape of NSCLC moving away from the old concept of a large indistinct histological entity to a combination of rare clinically relevant molecular subsets. Recently, a renewed interest has been emerging on the human epidermal growth factor-2 (HER2) pathway. Genetic aberrations of this signaling pathway have been reported over time to be associated in NSCLC with different sensitivity to the EGFR tyrosine kinase inhibitors, to have a possible prognostic role and more recently HER2 amplification has been emerged as a possible mechanism in EGFR-mutated tumors of acquired resistance to the EGFR tyrosine kinase inhibitors. In addition, dysregulation of the HER2 pathway, in particular HER2 mutations (mostly, in-frame exon 20 insertions), may represent a possible novel therapeutic target in NSCLC, paving the way for a new generation of targeted agents in NSCLC. Since anecdotal case reports of clinical activity of anti-HER2 agents in NSCLC patients with HER2 mutations, several targeted agents have been evaluated in HER2-mutated patients, generating a growing interest upon this oncogenic driver, leading to the design of molecularly selected trials with anti-HER2 compounds and the rediscover of hastily thrown out drugs, such as neratinib. The aim of this article is to provide an overview of the role of HER2 dysregulation in NSCLCs, trying to throw a light not only on the strengths but also the weaknesses of the studies conducted so far. It is a long way to the clinical implementation of these biomarkers and probably the increasing use of next generation sequencing techniques, the creation of large multi-institutional molecular testing platforms and the design of rationally based trials can get closer personalized medicine in NSCLC.
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Inoue Y, Matsuura S, Kurabe N, Kahyo T, Mori H, Kawase A, Karayama M, Inui N, Funai K, Shinmura K, Suda T, Sugimura H. Clinicopathological and Survival Analysis of Japanese Patients with Resected Non-Small-Cell Lung Cancer Harboring NKX2-1, SETDB1, MET, HER2, SOX2, FGFR1, or PIK3CA Gene Amplification. J Thorac Oncol 2015; 10:1590-1600. [PMID: 26536195 DOI: 10.1097/jto.0000000000000685] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
INTRODUCTION Gene amplification is an important genetic change in cancer cells. We investigated the prevalence, clinicopathological characteristics, and prognostic value of NKX2-1 (also known as TTF-1), SETDB1, MET, HER2, SOX2, FGFR1, and PIK3CA amplification in Japanese patients with non-small-cell lung cancer (NSCLC). METHODS The copy numbers of the seven above-mentioned genes were assessed using fluorescence in situ hybridization in a tissue microarray containing 282 surgically resected NSCLC specimens (164 adenocarcinoma [AC], 99 squamous cell carcinoma [SCC], and 19 others). Clinicopathological information were obtained from the medical records. RESULTS NKX2-1, SETDB1, MET, HER2, SOX2, FGFR1, and PIK3CA gene amplification were observed in 30 of 277 (10.8%), 16 of 280 (5.7%), 38 of 278 (13.7%), 8 of 270 (3.0%), 34 of 278 (12.2%), 18 of 282 (6.4%), and 53 of 278 (19.1%) cases, respectively. Coamplification was detected in 16 of 156 (10.3%) AC patients and 35 of 93 (37.6%) SCC patients (p < 0.0001). NKX2-1 amplification was significantly related to an AC histology (p = 0.004), whereas SOX2, FGFR1, and PIK3CA amplifications were related to a SCC histology (p < 0.0001). Within the ACs, NKX2-1 and SETDB1 amplifications were markers of a shorter survival period. A multivariate Cox proportional hazards model revealed that NKX2-1 amplification was an independent predictor of poor survival (hazard ratio, 2.938; 95% confidence interval, 1.434-6.022; p = 0.003). Coamplification had impact on patient outcome in AC but not in entire NSCLC and SCC. CONCLUSIONS The amplification status differed among the histological types of NSCLC. NKX2-1 amplification was an independent and the most practically important predictor of a poor prognosis among Japanese patients with AC.
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Affiliation(s)
- Yusuke Inoue
- *Department of Tumor Pathology, †Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan; ‡Department of Pathology, Hamamatsu Medical Center, Hamamatsu, Shizuoka, Japan; §First Department of Surgery, ‖Clinical Oncology, ¶Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
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Dahle-Smith Å, Stevenson D, Massie D, Murray GI, Dutton SJ, Roberts C, Ferry D, Osborne A, Clark C, Petty RD, Miedzybrodzka Z. Epidermal Growth Factor (EGFR) copy number aberrations in esophageal and gastro-esophageal junctional carcinoma. Mol Cytogenet 2015; 8:78. [PMID: 26478746 PMCID: PMC4609119 DOI: 10.1186/s13039-015-0181-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 10/01/2015] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Clinical trials of agents targeting epidermal growth factor receptor (EGFR) in esophageal carcinoma (EC) have indicated a minority subgroup responsive to anti-EGFR therapies. Other investigations suggest increases in EGFR copy number are associated with poor prognosis in EC, but have used a variety of different techniques and tested numbers remain small. A validated assay for EGFR copy number in EC is needed, to allow investigation of EGFR copy number gain as a predictive biomarker for the anti-EGFR responsive subgroup of patients. We developed a scoring system in EC based upon established systems for EGFR fluorescence in-situ hybridisation (FISH) in lung cancer, and applied this in a series of 160 UK patients with advanced EC. RESULTS Dual colour FISH on formalin fixed paraffin embedded (FFPE) biopsies were scored independently by two operators as: disomy (score = 1), low trisomy (score = 2), high trisomy (score = 3), low polysomy (score = 4), high polysomy (score = 5) and amplification (score = 6). EGFR FISH positive cases (scores 5 and 6) were found in 32/160 (20 %) tumours, with high polysomy in 22 (13.8 %) and amplification in 10 (6.3 %). Two independent operator scores for FISH positivity were 100 % concordant. EGFR FISH positive status was not associated with clinic-pathological features. EGFR amplification was associated with worse survival (HR = 2.64, 95 % CI 1.04 to 6.71, p = 0.03). CONCLUSION Our FISH scoring system for EGFR in advanced EC identifies a significant subgroup (20.0 %) of FISH positive patients. EGFR amplification, which is found in 6.3 %, is associated with poor survival. It is not known if there is a role for EGFR targeted treatment in this subgroup of patients, however we are now utilising this EGFR FISH assay and scoring system in biopsies from clinical trials utilising anti-EGFR targeted therapies.
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Affiliation(s)
- Åsa Dahle-Smith
- />Division of Applied Medicine, University of Aberdeen, Aberdeen, AB25 2ZD UK
| | - David Stevenson
- />Department of Medical Genetics, Aberdeen Royal Infirmary, Aberdeen, AB25 2ZD UK
| | - Doreen Massie
- />Department of Medical Genetics, Aberdeen Royal Infirmary, Aberdeen, AB25 2ZD UK
| | - Graeme I. Murray
- />Division of Applied Medicine, University of Aberdeen, Aberdeen, AB25 2ZD UK
- />Department of Pathology, University of Aberdeen, Aberdeen, AB25 2ZD UK
| | - Susan J. Dutton
- />Centre for Statistics in Medicine (CSM), Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Windmill Road, Oxford, OX3 7LD UK
| | - Corran Roberts
- />Centre for Statistics in Medicine (CSM), Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Windmill Road, Oxford, OX3 7LD UK
| | - David Ferry
- />Eli Lilly and Company, 440 Route 22 East, Bridgewater, NJ 08807 USA
| | - Aileen Osborne
- />Department of Medical Genetics, University of Aberdeen, Aberdeen, AB25 2ZD UK
| | - Caroline Clark
- />Department of Medical Genetics, Aberdeen Royal Infirmary, Aberdeen, AB25 2ZD UK
| | - Russell D. Petty
- />Division of Applied Medicine, University of Aberdeen, Aberdeen, AB25 2ZD UK
| | - Zosia Miedzybrodzka
- />Division of Applied Medicine, University of Aberdeen, Aberdeen, AB25 2ZD UK
- />Department of Medical Genetics, Aberdeen Royal Infirmary, Aberdeen, AB25 2ZD UK
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Significance of EGFR signaling pathway genetic alterations in radically resected non-small cell lung cancers from a Polish cohort. One institutional study. Adv Med Sci 2015; 60:277-86. [PMID: 26118982 DOI: 10.1016/j.advms.2015.05.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 05/28/2015] [Accepted: 05/29/2015] [Indexed: 12/12/2022]
Abstract
PURPOSE We evaluated the distribution and clinical impact of EGFR, KRAS and HER2 copy number gains and EGFR, KRAS and BRAF activating mutations in resected non-small cell lung cancers (NSCLCs) from 151 Polish patients. MATERIALS AND METHODS Quantitative PCR and DNA sequencing were used for copy number evaluation and mutational analysis, respectively. RESULTS An increased EGFR CN was found in 21.2% of the tumors, more commonly of the non-squamous histology (P=0.029), larger in size (P=0.004) and those obtained from women (P=0.040). HER2 copy gain was observed in 21.8% of the patients, more frequently with lymph node metastases (P=0.048) and stage IIIA disease (P=0.061). KRAS gain was found in 29.3% of the tumors, and was not associated with patients' clinicopathological features. No BRAF mutations were found. EGFR and KRAS mutation frequency and associations with clinicopathological characteristics did not differ significantly from those previously described for the NSCLC patients of Caucasian ethnicity. Strong associations existed between most of the analyzed alterations. In the multivariate model, EGFR mutations constituted an independent prognostic factor of the disease recurrence in adenocarcinoma patients (HR 7.20; 95%CI 1.31-39.48; P=0.023), while an increased EGFR copy number tended to indicate a shorter overall survival (HR 4.85; 95%CI 0.92-25.58; P=0.062). CONCLUSIONS EGFR pathway genes alterations are frequent in NSCLCs from Polish patients and have a prognostic potential for patients' clinical outcome after a curative tumor resection. Gene CN evaluation by quantitative PCR provides comparable results and enables assay standardization, yet the optimal scoring system needs to be developed.
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