Abstract P3-05-13: Estrogen-independent growth of ESR1-mutant breast cancer cells requires CDK4/6

Abstract

Abstract A recent breakthrough in cancer treatment has been the development of highly specific cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. CDK4/6 inhibitors, such as palbociclib, prevent cell cycle progression from growth phase (G1) to the DNA synthesis (S) phase of the cell cycle. Palbociclib, however, is only approved for first-line treatment of patients with estrogen receptor positive (ER+) breast cancer in combination with an aromatase inhibitor, letrozole. Approximately 20% of metastatic breast cancer patients, harbor an activating mutation in the ligand-binding domain (LBD) of the estrogen receptor gene, ESR1, which confers resistance to estrogen deprivation. It is unclear whether tumors harboring these endocrine treatment-associated mutations will also respond to CDK4/6 inhibition. We have found that estrogen-independent growth of ESR1 -mutant breast cancer cells requires CDK4/6. Thus, ESR1-mutant breast cancer cells are sensitive to CDK4/6 inhibition. Mechanistically, ERS1 LBD-mutant cells upregulate key mediators of the G1-S cell cycle transition. Furthermore, the sensitivity of ESR1-mutant breast cancer cells to CDK4/6 inhibition requires RB1. While cells expressing RB1 respond to CDK4/6 inhibition, knockout of RB1 via CRISPRs enables ESR1-mutant breast cancer cells to resist combined estrogen depletion and CDK4/6 inhibition. Our studies suggest that tumors harboring ESR1 LBD mutations and an intact RB1 will respond to combined CDK4/6 inhibition and estrogen deprivation. Citation Format: Luo F, Le X, Jeselsohn R, Brown M, Garraway L. Estrogen-independent growth of ESR1-mutant breast cancer cells requires CDK4/6. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-13.