Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors
Open Access
- 21 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 124 (7), 1249-1259
- https://doi.org/10.1038/s41416-020-01257-x
Abstract
Background Human epidermal growth factor 2 (HER2/ERBB2) is frequently amplified/mutated in cancer. The tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib are FDA-approved for the treatment of HER2-positive breast cancer. Direct comparisons of the preclinical efficacy of the TKIs have been limited to small-scale studies. Novel biomarkers are required to define beneficial patient populations. Methods In this study, the anti-proliferative effects of the three TKIs were directly compared using a 115 cancer cell line panel. Novel TKI response/resistance markers were identified through cross-analysis of drug response profiles with mutation, gene copy number and expression data. Results All three TKIs were effective against HER2-amplified breast cancer models; neratinib showing the most potent activity, followed by tucatinib then lapatinib. Neratinib displayed the greatest activity in HER2-mutant and EGFR-mutant cells. High expression of HER2, VTCN1, CDK12, and RAC1 correlated with response to all three TKIs. DNA damage repair genes were associated with TKI resistance. BRCA2 mutations were correlated with neratinib and tucatinib response, and high expression of ATM, BRCA2, and BRCA1 were associated with neratinib resistance. Conclusions Neratinib was the most effective HER2-targeted TKI against HER2-amplified, -mutant, and EGFR-mutant cell lines. This analysis revealed novel resistance mechanisms that may be exploited using combinatorial strategies.Keywords
Funding Information
- Irish Research Council (EPSPD/2020/24, EPSD/2020/24)
- Cancer Clinical Research Trust (Charity no. CHY12210) Puma Biotechnology Inc
- Cancer Clinical Research Trust (Charity no. CHY12210) Puma Biotechnology Inc.
This publication has 51 references indexed in Scilit:
- An androgen receptor mutation in the MDA-MB-453 cell line model of molecular apocrine breast cancer compromises receptor activityEndocrine-Related Cancer, 2012
- The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivityNature, 2012
- Inactivation of Rac1 reduces Trastuzumab resistance in PTEN deficient and insulin-like growth factor I receptor overexpressing human breast cancer SKBR3 cellsCancer Letters, 2011
- Activated Phosphoinositide 3-Kinase/AKT Signaling Confers Resistance to Trastuzumab but not LapatinibMolecular Cancer Therapeutics, 2010
- EGFRMutation Is a Better Predictor of Response to Tyrosine Kinase Inhibitors in Non–Small Cell Lung Carcinoma Than FISH, CISH, and ImmunohistochemistryAmerican Journal of Clinical Pathology, 2010
- Combination of cetuximab with chemoradiation, trastuzumab or MAPK inhibitors: mechanisms of sensitisation of cervical cancer cellsBritish Journal of Cancer, 2009
- FDA Drug Approval Summary: Lapatinib in Combination with Capecitabine for Previously Treated Metastatic Breast Cancer That Overexpresses HER-2The Oncologist, 2008
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- Did the Four Human Cancer Cell Lines DLD-1, HCT-15, HCT-8, and HRT-18 Originate from One and the Same Patient?Cancer Genetics and Cytogenetics, 1998
- Studies of the HER-2/ neu Proto-Oncogene in Human Breast and Ovarian CancerScience, 1989