Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors.

Autor: Conlon NT; National Institute of Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland. neil.conlon@dcu.ie., Kooijman JJ; Netherlands Translational Research Center B.V., Kloosterstraat 9, 5349 AB, Oss, The Netherlands., van Gerwen SJC; Netherlands Translational Research Center B.V., Kloosterstraat 9, 5349 AB, Oss, The Netherlands., Mulder WR; Netherlands Translational Research Center B.V., Kloosterstraat 9, 5349 AB, Oss, The Netherlands., Zaman GJR; Netherlands Translational Research Center B.V., Kloosterstraat 9, 5349 AB, Oss, The Netherlands., Diala I; Puma Biotechnology, Inc., 10880 Wilshire Boulevard, Suite 2150, Los Angeles, CA, 90024, USA., Eli LD; Puma Biotechnology, Inc., 10880 Wilshire Boulevard, Suite 2150, Los Angeles, CA, 90024, USA., Lalani AS; Puma Biotechnology, Inc., 10880 Wilshire Boulevard, Suite 2150, Los Angeles, CA, 90024, USA., Crown J; National Institute of Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland.; Department of Medical Oncology, St Vincent's University Hospital, Dublin, Ireland., Collins DM; National Institute of Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2021 Mar; Vol. 124 (7), pp. 1249-1259. Date of Electronic Publication: 2021 Jan 21.
DOI: 10.1038/s41416-020-01257-x
Abstrakt: 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.
Databáze: MEDLINE
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