Abstract
Clinical resistance mechanisms to CDK4/6 inhibitors in HR+ breast cancer have not been clearly defined. Whole exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of ER expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Besides inactivation of RB1, which accounts for ∼5% of resistance, seven of these mechanisms have not been previously identified as clinical mediators of resistance to CDK4/6 inhibitors in patients. Three of these—RAS activation, AKT activation, and AURKA activation—have not to our knowledge been previously demonstrated preclinically. Together, these eight mechanisms were present in 80% of resistant tumors profiled and may define therapeutic opportunities in patients.
Significance We identified eight distinct mechanisms of resistance to CDK4/6 inhibitors present in 80% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ MBC.
Footnotes
Competing Financial Interest Statement: SAW has served as an advisor/consultant to Foundation Medicine (consulting); Eli Lilly (consulting); Puma Biotechnology (consulting); and InfiniteMD (consulting, equity) and receives institutional research funding from Genentech. AGW receives institutional research funding from Genentech and MacroGenics. QC receives institutional research funding from Abbvie, Amgen, Astra Zeneca, Aurka, Boheringer Ingelheim, BMS, Celgene, Debio, Esparas, Eli Lilly, GSK, Merck, Novartis, Roche, TP Therapeutics; as well as advisory fess and hororaria from Abbvie, Astra Zeneca, Bohehringer Ingelheim, BMS, Eli Lilly, Merck, Novartis, Roche, Takeda. SMT has received institutional research support from Merck, Bristol-Myers Squibb, Exelixis, Eli Lilly, Pfizer, Novartis, AstraZeneca, Eisai, Nektar, Odenate, Sanofi, Immunomedics, Cyclacel, and Genentech; and has served as a consultant/advisor for Genentech, Eli Lilly, Novartis, Pfizer, Celldex, Paxman, Seattle Genetics, Nektar, Immunomedics, Nanostring, Daiichi-Sankyo, Bristol-Meyers Squibb, Sanofi, Abbvie, Athenex, AstraZeneca, Eisai, Puma, and Merck. NUL is a consultant for Puma Biotechnology, Seattle Genetics, and Daichii Sankyo, and received institutional research funding from Merck, Pfizer, Genentech, Array Biopharma, Novartis and Seattle Genetics. EPW has served as a consultant/advisor for InfiniteMD, Genentech, and Eli Lilly. NW was previously a stockholder and consultant for Foundation Medicine; has been a consultant/advisor for Novartis and Eli Lilly; and has received sponsored research support from Novartis and Puma Biotechnology. XG, SP, RM, LML, XSY, CPU, GJO, VMJ, JRS, PSS, LAG, and SB were employees and shareholders of Eli Lilly and Company at the time of manuscript preparation. Except as indicated by the author affiliations, none of these entities had any role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript.
