RRC ID 77039
Author Conlon NT, Kooijman JJ, van Gerwen SJC, Mulder WR, Zaman GJR, Diala I, Eli LD, Lalani AS, Crown J, Collins DM.
Title Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors.
Journal Br J Cancer
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.
Volume 124(7)
Pages 1249-1259
Published 2021-3-1
DOI 10.1038/s41416-020-01257-x
PII 10.1038/s41416-020-01257-x
PMID 33473169
PMC PMC8007737
MeSH Apoptosis Biomarkers, Tumor / genetics* Cell Proliferation Gene Expression Regulation, Neoplastic / drug effects* Humans Lapatinib / pharmacology Neoplasms / drug therapy Neoplasms / genetics Neoplasms / pathology* Protein Kinase Inhibitors / pharmacology* Quinolines / pharmacology Receptor, ErbB-2 / antagonists & inhibitors* Trastuzumab / pharmacology Tumor Cells, Cultured
IF 5.791
Human and Animal Cells II-18(RCB2093)