Abstract B35: Palbociclib treatment activates FAK and use of palbociclib in combination with the FAK inhibitor PF-562,271 enhances antitumor activity in ER-positive breast cancer cells

Abstract

Cell survival and proliferation is tightly regulated by a number of interacting coordinated signaling proteins including the cyclin-dependent kinases (CDK). Palbociclib, a CDK4/6 inhibitor, has recently been shown to be very effective in the treatment of estrogen receptor (ER) positive breast cancer; however, many patients develop an acquired resistance through as yet incompletely characterized mechanisms. One recently proposed mechanism is compensation by CDK2 (Herrera-Abreu et al., Can Res 2016;76:2301). Focal adhesion kinase (FAK) is a tyrosine kinase that plays a central role in signaling pathway crosstalk and cell survival and invasion. FAK has been previously shown to activate CDK2 in hepatocytes (Flinder et al., J Cell Phys 2013;228:1304), and given its important role in mediating cell survival, we were interested in determining whether FAK-mediated upregulation of CDK2 occurs in palbociclib-treated breast cancer cells, thereby limiting its efficacy. ER-positive MCF7, MDA-MB-134VI, and T47D breast cancer cell lines were thus treated with increasing doses of palbociclib. We observed dose-dependent increases in phospho-FAK Y397, a marker of the active kinase, following palbociclib treatment. We thus used PF-562,271, a selective FAK tyrosine kinase inhibitor, in combination with palbociclib and, not surprisingly, observed an enhanced ability to inhibit cell viability as compared to use of either drug alone. This was concomitant with observed increases in the CDK4/6 inhibitor p27, and with decreases in phospho-RB, which are indicative of reduced CDK2 activity, following treatment with PF-562,271. Our results highlight an unexpected side effect of palbociclib treatment, namely FAK activation, which could potentially contribute to resistance due to activation of CDK2 and inhibition of p27. The mechanism by which palbociclib activates FAK is currently under investigation. Citation Format: Grant Howe, Victoria Allen, Christina L. Addison. Palbociclib treatment activates FAK and use of palbociclib in combination with the FAK inhibitor PF-562,271 enhances antitumor activity in ER-positive breast cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B35.