Abstract 315: Identification of distinct and targetable mechanisms of acquired resistance to CDK4/6 inhibitors

Abstract

Abstract Recently, three CDK4/6 inhibitors were approved by FDA and became effective treatments for ER+ breast cancer patients. However, most if not all patients eventually progress on treatment . To identify mechanisms associated with acquired resistance to CDK4/6 inhibitors, we derived 15 CDK4/6i-resistant variants from human cancer cell lines highly sensitive to CDK4/6 inhibition with abemaciclib or palbociclib. Transcriptome and proteomic profiling of the derivatives revealed four general classes of alteration: decreased RB1, increased CCNE1 or CCNE2, increased ERK phosphorylation, and increased Aurora-A expression. A drug screen was employed to identify drugs or abemaciclib-drug combinations that could suppress growth of the resistant variants. Inhibitors of Aurora-A, Chk1 and the Ras-MAPK pathway were effective for the treatment of the respective classes of resistant derivative. Importantly, Rb loss, Aurora-A amplifications and Ras mutations were all observed as recurrent alterations in biopsies from ER+ breast cancer patients after progression on CDK4/6 inhibitors (1,2). Together these data demonstrate that cancer cells can escape from suppression by CDK4/6 drugs via multiple mechanisms and suggest clinically available therapeutic strategies to treat different classes of resistance. 1. S Wander et al, AACR, 2018 2. R Condorelli et al, Annals of Oncology, vol 29, issue 3, 640-645, 2017 Citation Format: Stephen Parsons. Identification of distinct and targetable mechanisms of acquired resistance to CDK4/6 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 315.