Mantle cell lymphoma (MCL) is a cyclin D1 over-expressing B cell lymphoma which displays unregulated cell cycle progression driven by increased cyclin-dependent kinase (CDK) activity. We are investigating selective small molecule CDK inhibitors as potential therapeutics in MCL. AZD5438, flavopiridol, PD-0332991 and SNS-032 have distinct efficacies against different groups of CDKs. We hypothesize that inhibiting CDK-7 and -9 will be more effective in causing cell death in MCL than inhibiting CDK-1,-2,-4 and- 6. In Jeko-1 cells, AZD5438 and flavopiridol displayed time- and dose-dependent inhibition of cell proliferation, inhibition of the phosphorylation of CDK substrates, and G1 cell cycle arrest; while PD-0332991 showed a strong cytostatic effect by inhibiting cell proliferation and arresting cells at the G1 phase, but not inducing apoptosis to the same extent as flavopiridol and AZD5438. In addition, AZD5438, flavopiridol and SNS-032 induced caspase-3 activation and down regulation of Mcl-1, but no apoptotic effect was shown in PD-0332991 treated cells. These differential effects may be associated with essential survival functions conferred by genes regulated by CDK7/9 including the pro-survival protein Mcl-1. However, there were no apoptotic effects observed with any of these CDK inhibitors in Granta-519 cells, which may due to high Bcl-2 levels. We are now exploring combinations of CDK7/9 inhibitors with a small molecule inhibitor of Bcl-2 function. We expect CDK7/9 inhibition will reduce Mcl-1 expression at the transcriptional level and thereby sensitize both Jeko-1 and Granta-519 cells to Bcl-2 inhibition. We will also investigate Mcl-1 and Bcl-2 levels in clinical samples to see if there is a correlation with outcomes. Our expectation is that Mcl-1/Bcl-2 levels may ultimately become a useful prognostic and predictive biomarker in MCL.

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 3050. doi:1538-7445.AM2012-3050

©2012 American Association for Cancer Research
2012