The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia

Abstract

Translocations of the mixed lineage leukemia (MLL) gene occur in 60% to 80% of all infant acute leukemias and are markers of poor prognosis. MLL-AF9 and other MLL fusion proteins aberrantly recruit epigenetic regulatory proteins, including histone deacetylases (HDAC), histone methyltransferases, bromodomain-containing proteins, and transcription elongation factors to mediate chromatin remodeling and regulate tumorigenic gene expression programs. We conducted a small-molecule inhibitor screen to test the ability of candidate pharmacologic agents targeting epigenetic and transcriptional regulatory proteins to induce apoptosis in leukemic cells derived from genetically engineered mouse models of MLL-AF9-driven acute myeloid leukemia (AML). We found that the CDK inhibitor dinaciclib and HDAC inhibitor panobinostat were the most potent inducers of apoptosis in short-term in vitro assays. Treatment of MLL-rearranged leukemic cells with dinaciclib resulted in rapidly decreased expression of the prosurvival protein Mcl-1, and accordingly, overexpression of Mcl-1 protected AML cells from dinaciclibinduced apoptosis. Administration of dinaciclib to mice bearing MLL-AF9-driven human and mouse leukemias elicited potent antitumor responses and significantly prolonged survival. Collectively, these studies highlight a new therapeutic approach to potentially overcome the resistance of MLL-rearranged AML to conventional chemotherapies and prompt further clinical evaluation of CDK inhibitors in AML patients harboring MLL fusion proteins. Cancer Res; 76(5); 1158-69. Ó2015 AACR.

Dinaciclib induces immunogenic cell death and enhances anti-PD1–mediated tumor suppression

“…Here, we demonstrate that the CDK inhibitor dinaciclib (also known as MK-7965 and SCH727965) is capable of eliciting ICD. Dinaciclib is a potent CDK1, -2, -5, and -9 inhibitor that induces apoptosis in different tumor cells and has been shown to be clinically active in refractory chronic lymphocytic leukemia (38)(39)(40)(41)(42)(43)(44)(45)(46). These CDK targets regulate the cell cycle (CDK1, -2), control actin polymerization and neuronal function (CDK5), and regulate RNA-polymerase II (CDK9), and their repression can affect T cell proliferation and migration (47).…”

Dual targeting of MCL1 and NOXA as effective strategy for treatment of mantle cell lymphoma

“…MCL1 is characterized by a relatively short half‐life and such proteins can selectively be reduced following CDK9 inhibition (Baker et al , ). The broad‐spectrum CDK inhibitor Dinaciclib was shown to effectively suppress MCL1 protein expression and to have antitumour activity in a variety of haematological malignancies, most probably due to transcriptional repression as a result of dephosphorylation of the RNA Pol II subunit RPB1 (P‐RPB1) mediated by CDK9 inhibition (Bose et al , ).…”

Ras oncogene-independent activation of RALB signaling is a targetable mechanism of escape from NRAS(V12) oncogene addiction in acute myeloid leukemia

“…It is possible that dinaciclib-mediated inhibition of CDK1, another protein that was enriched in relapse NRI AMLs, or CDK9, an alternate survival pathway for MLL-rearranged AMLs, 47 contributes to the anti-leukemic activity of dinaciclib. In fact, drugs that target multiple pathways may reduce the ability of AML cells to coopt alternate resistance pathways.…”