ABT-348 is a novel, potent and orally bioavailable inhibitor of the Aurora kinases as well as the VEGF and PDGF families of receptor tyrosine kinases. ABT-348 is broadly efficacious preclinically as a single agent against a wide range of tumor types and is currently in Phase I/II clinical trials. Several published studies have supported the potential utility of combining targeted anti-proliferative agents with cytotoxic chemotherapies. Herein, the efficacy of combining the neocytotoxic agent, ABT-348, with CDK4/6 inhibition in the treatment of solid tumor cells has been evaluated. Inhibition of CDK4/6 via siRNA elicits a potent cytostatic response in cells that harbor a wild-type, functional RB. We demonstrate that features of cellular senescence are induced in human tumor cells with siRNAs targeting both CDK4 and CDK6. Dual inhibition of CDK4 and CDK6 is required for antiproliferative activity in most cancer cell lines and this is not accompanied by induction of apoptosis. In RB wild-type cells, CDK4/6 inhibition antagonizes the activity of ABT-348 by inducing G0/G1 arrest. Conversely, CDK4/6 inhibition does not alter the therapeutic response of RB-deficient cells to ABT-348, indicating that the effects of ABT-348 are dependent on cells progressing into mitosis. A preponderance of evidence from previous publications and our studies indicate that CDK4/6 inhibition attenuates the cellular response to cytotoxic chemotherapies in RB wild-type cells providing a potential to expand the therapeutic window for ABT-348. Thus combination with ABT-348 and a CDK4/6 inhibitor may provide an opportunity to selectively target RB mutant cells.
Citation Format: Jun Guo, Michael L. Curtin, Zehan Chen, Daniel H. Albert, Paul Tapang, Yujia Dai, Mia-Ha Bui, Peter Kovar, Michael R. Michaelides, Keith B. Glaser, Chris Tse, O. Jameel Shah. ABT-348 in combination with inhibition of CDK4/6 highlights a strategy to target RB mutant cells while sparing RB wild-type cells. [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 3450. doi:10.1158/1538-7445.AM2013-3450