Dual CDK2 and CDK4/6 inhibition suppresses Rb/E2F signaling and enhances anti-leukemic activity in acute myeloid leukemia.

Abstract

The cyclin-dependent kinase 6 (CDK6) is a central regulator of cell cycle progression and an important contributor to the development of acute leukemia, particularly in poor prognosis subtypes. Preclinical studies have demonstrated activity of CDK6-targeting drugs in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), but clinical trials with CDK4/6 inhibitors as monotherapy were disappointing. In contrast, clinical efficacy was observed for the combination of the dual CDK4/6 inhibitor, palbociclib, with chemotherapy in pediatric acute leukemia and lymphoma patients. We sought to evaluate the potential of CDK6 inhibition to sensitize AML cells to both standard-of-care and novel targeted therapies. We found the CDK2- targeting drug, tegtociclib, to be particularly effective in potentiating the inhibitory effects of CDK4/6 inhibitors against acute leukemia cells. While similar strategies have been considered for solid tumors where CDK4/6 targeted agents may work as monotherapy, we have discovered a unique and novel approach to introduce this class of drugs to acute leukemias. Our results also demonstrate that synergy between these agents, as has been previously shown in breast cancer, is also observed in acute leukemia and correlates with suppression of the Rb/E2F axis and inhibition of cell cycle progression. The universality between the underlying mechanisms of synergy for CDK2 inhibitors combined with CDK4/6 inhibitors in breast cancer and AML warrants further evaluation in other malignancies characterized by dependencies on these CDK subtypes.