Abstract LB-249: Characterization of a novel potent and selective CDK4/6 inhibitor and a resistance mechanism

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL CDK4 and CDK6 are two highly related cyclin D-dependent cell cycle regulatory kinases. CDK4/6 activity promotes G1 to S phase transition by phosphorylating the retinoblastoma (Rb) tumor suppressor protein. Here, we report the characterization of a potent, selective and orally-available small molecule inhibitor of CDK4/6 for treating Rb-positive cancer. The inhibitor was over 1000-fold more potent in inhibiting CDK4 than CDK1. It also showed Rb-dependent anti-proliferative activity both in cancer cell lines and in xenograft tumor models. A greater degree of variation in sensitivity to the inhibitor was observed in colon cancer cell lines compared to the other cell lines tested. To understand this difference in sensitivity, we isolated CDK4/6 inhibitor-resistant colon cancer cells by growing sensitive cells in the presence of the inhibitor. Gene expression in the parental and the resistant cells was analyzed and compared. Cyclin E1, a CDK2 cyclin, was found to be the most significantly overexpressed gene in the resistant cells. Consistent with this, CDK2-associated cyclin E1 protein and CDK2 kinase activity were also significantly increased in the cells. These results suggest that high expression of cyclin E1 may make tumors less sensitive to CDK4/6 inhibition and could be a potential sensitivity marker for patient selection for treatment with a CDK4/6 inhibitor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-249. doi:1538-7445.AM2012-LB-249