Abstract A41: Targeting the ARK5/MYC axis to develop second generation CDK4/6 inhibitors

Abstract

Abstract Inhibition of cyclin dependent kinases CDK4/6 is an emerging therapeutic approach in myeloma and other cancers. A direct link between MYC and the cell cycle machinery exists through its ability to directly transactivate the CCND1 and CCNE genes. Deregulated MYC expression is linked to increased cyclin A, cyclin E expression and activation of CDK4 via its direct target gene CDC25. We describe a novel mechanism of MYC silencing that is therapeutically targeted by small molecule inhibitors. ARK5 (AMPK-related protein kinase 5), a novel member of the human AMPK family, represses MYC and MYC-driven gene expression, leading to rapid induction of apoptosis and cell cycle arrest. RNAi loss of function studies confirm that ARK5 decreases MYC expression via post-translational de-acetylation by NAD-dependent deacetylase sirtuin 1 (SIRT1). In ARK5 over-expressing primary myeloma cells and cell lines, treatment with dual ARK5 and CDK4/6 inhibitor ON123300 resulted in down-regulation of pS6K, Rb and MYC, resulting in cell cycle arrest followed by apoptosis in vitro. Treatment of MM tumor-bearing mice with ON123300 significantly decreased the growth of tumors as opposed to control treated mice and was well tolerated, with no significant weight loss. The CDK4/6 selective inhibitor PD0332991 in contrast does not inhibit the ARK5 or mTOR/pS6K pathways. We hypothesized that the modest activity for the current class of CDK4/6 inhibitors could be the result of a narrow kinase inhibition profile and incomplete targeting of critical onco-kinases, resulting in cytostatic rather than cytotoxic effects. This is the first report showing that dual CDK4/6 and ARK5 inhibitor ON123300 has significant effects on mTOR and MYC. In summary, our results demonstrate a novel mechanistic connection between ARK5 and SIRT1 in the regulation of MYC in MM cells. Our data showing potent cytotoxicity of ARK5 inhibition along with inhibition of MYC and mTOR signaling provides the foundation for further development of ARK5 inhibitors and second generation CDK inhibitors such as ON123300 for MM and potentially other MYC over expressing cancers. Citation Format: Samir Parekh, Deepal Perumal, Pei Yu Kuo, Violetta Leshchenko, Zewei Jiang, Ajai Chari, Hearn Jay Cho, Sundar Jagannath, E. Premkumar Reddy. Targeting the ARK5/MYC axis to develop second generation CDK4/6 inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A41.