Abstract 4557: Expression of p16 in colon cancer and cyclin D1 in gastric cancer predicts response to CDK4/6 inhibition in vitro

Abstract

Abstract Background: Cyclin-dependent kinases (CDKs) play a significant role in regulating cell cycle progression through association with cyclins. CDK4 and CDK6 interact with cyclin D1 to mediate hyperphosphorylation of retinoblastoma (Rb) during early G1 phase. Palbociclib is a highly selective inhibitor of CDK4 and CDK6 which functions by blocking pRb phosphorylation resulting in G1 arrest in sensitive cell lines. We evaluated the effect of palbociclib in gastric and colon cancer cell lines to explore potential biomarkers of response and to guide patient selection in colon and gastric cancer. Methods: Panels of 17 gastric and 27 colon cancer cell lines were exposed in vitro to palbociclib over various concentrations to generate dose response curves. Analysis of variance (ANOVA) was used to identify differentially expressed genes between sensitive and resistant cell lines. Genes identified by ANOVA and effects of palbociclib on pRB were analyzed via western blot. Results: Palbociclib was found to have potent anti-proliferative activity in the low nanomolar range (< 150 nM) for 14 of the 44 gastric and colon cancer cell lines tested. In gastric cancer, cyclin D1-amplified cells cells expressed greater sensitivity to the compound when compared to cyclin D1-negative cells. HER2 amplified cell lines were also statistically more sensitive than HER2 negative cells. Combination studies with palbociclib and trastuzumab demonstrated significant synergy in HER2 amplified gastric cancer models. Furthermore, cyclin E emerged as a biomarker for resistance to the compound in gastric cancers. Contrary to observations made in other cancers, expression levels of p16 (CDK4 inhibitor) and p21 (CDK2 inhibitor) in colon cancer indicated that p16 loss and p21 gain predict for resistance rather than sensitivity to CDK4 and CDK6 inhibition. Conclusions: Palbociclib demonstrates anti-proliferative activity in several gastric and colon cancer cell lines. Molecular markers found to predict for sensitivity to this agent enhance patient selection for future clinical studies of palbociclib. Citation Format: Zev A. Wainberg, Ann Yufa, Adrian Anghel, Amy M. Rogers, Tin Manivong, Shahriar Adhami, Habib Hamidi, Dylan Conklin, Richard S. Finn, Dennis J. Slamon. Expression of p16 in colon cancer and cyclin D1 in gastric cancer predicts response to CDK4/6 inhibition in vitro. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4557. doi:10.1158/1538-7445.AM2014-4557