Cell growth is regulated by the activity of certain cyclin-dependent kinases (CDKs), including CDK4 and CDK6 (hereafter CDK4/6), which specifically regulate cell cycle progression through the G1 restriction point. These CDKs act with the D-type cyclins to phosphorylate and inactivate the retinoblastoma (Rb) tumor suppressor protein, which in turn enables cell cycle progression from G1 to S phase. LY2835219 is a selective inhibitor of CDK4/6 with IC50 of 2 and 10 nM for CDK4 and CDK6, respectively. The current study evaluates the activity of LY2835219 in preclinical models of human cancer including non-small cell lung cancer (NSCLC), melanoma, mantle cell lymphoma (MCL), and ovarian cancer. A secondary focus of this study is to identify potential predictive biomarkers for response to LY2835219 in NSCLC, melanoma, and other cancers. For NSCLC, increased sensitivity to LY2835219 is associated both in vitro and in vivo with KRAS mutations. For established melanoma cell lines, similar levels of in vitro sensitivity are observed in different genetic subtypes. Accordingly, LY2835219 shows single-agent activity in the A375 melanoma xenograft model with daily oral dosing at 45 or 90 mg/kg. For MCL, durable growth inhibition of subcutaneously implanted xenografts is achieved with daily oral dosing at 50mg/kg. Finally, in an intra-peritoneal model that recapitulates clinical features of human ovarian cancer, LY2835219 not only inhibits tumor growth but also increases survival. These studies suggest that LY2835219 may have potential therapeutic application in the treatment of human cancers with specific molecular alterations. Citation Format: Jack A. Dempsey, Edward M. Chan, Teresa F. Burke, Richard P. Beckmann. LY2835219, a selective inhibitor of CDK4 and CDK6, inhibits growth in preclinical models of human cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-122. doi:10.1158/1538-7445.AM2013-LB-122