Abstract MS2-1: Mechanisms of resistance to CDK4/6 inhibitors and new therapeutic approaches

Abstract

Abstract Activation of the CDK4/6 kinases is a well-established mechanism whereby estrogens and other mitogens drive breast cancer growth. ATP competitive inhibitors of the CDK4/6 kinases have had a transformational impact on the clinical approach to ER+ breast cancer patients. However, with prolonged CDK4/6i therapy, most tumors ultimately develop resistance. Unlike the case for acquired resistance to many other targeted therapies, CDK4/6i resistance does not appear to be occur through mutations of the drug target. Second site, missense mutations in CDK4 and CDK6 have not been identified in either preclinical resistance screens or clinical biopsies of resistant tumors. This raises several questions including: (1) what are the genetic alterations and pathways that mediate resistance to CDK4/6i therapy in breast cancer, (2) what therapeutic approaches are effective after tumors have developed resistance to CDK4/6i, and (3) what can these understandings about resistance teach us about the underlying basis for sensitivity to CDK4/6i therapy. In this talk, published and unpublished data on mechanisms of resistance to CDK4/6i will be reviewed to elucidate how tumors can either restore CDK4/6 activity or else bypass the requirement for these G1 checkpoint kinases. Data on potential vulnerabilities for each class of drug-resistant tumors will then be discussed. Finally, the findings on resistance will be used to revisit the original understandings on the basis for CDK4/6i sensitivity and how that informs the ongoing use of these drugs in other settings and with more effective combinations that might suppress the emergence of resistance. Citation Format: S Chandarlapaty. Mechanisms of resistance to CDK4/6 inhibitors and new therapeutic approaches [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr MS2-1.