LYMPHOID NEOPLASIA Prolonged early G1 arrest by selective CDK4/CDK6 inhibition sensitizes

(CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibi-tors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit prolifera-tion and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G1 arrest (pG1) by CDK4/CDK6 inhibi-tion halts gene expression in early-G1 and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G1 block leads to S-phase synchroniza-tion (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect my-eloma cells from apoptosis is markedly re-duced in pG1 and further in pG1-S in re-sponse to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coor-dinated loss of IRF4 and gain of Bim sensi-tize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in coop-eration with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibi-tion further augments tumor-specific bor-tezomib killing in myeloma xenografts. Re-versible inhibition of CDK4/CDK6 in sequential combination therapy thus repre-sents a novel mechanism-based cancer therapy. (Blood. 2012;120(5):1095-1106