CDK8/19 Inhibition Attenuates G1 Arrest Induced by BCR-ABL Antagonists and Accelerates Death of Chronic Myelogenous Leukemia Cells

Imatinib and other selective inhibitors of BCR-ABL are the mainstay of chronic myelogenous leukemia (CML) treatment, but resistance to these drugs limits their efficacy. Known resistance mechanisms include ABL mutations, activation of compensatory signaling pathways, and the induction of quiescence that protects CML cells from apoptosis. CDK8/19 Mediator kinases that regulate transcriptional reprogramming have been implicated in the development of resistance to different drugs. We have investigated the effects of CDK8/19 inhibition on CML response to BCR-ABL inhibitors. Selective CDK8/19 inhibitors Senexin B and SNX631 strongly increased the induction of apoptosis in K562 cells treated with imatinib or other BCR-ABL inhibitors. Imatinib induced G1 arrest along with upregulation of p27Kip1, but these effects were suppressed by CDK8/19 inhibition. Senexin B also prevented the induction of G1 arrest and protection from imatinib-induced apoptosis of K562 cells by inducible p27Kip1 expression, suggesting that CDK8/19 activity potentiates both the transcription and function of p27Kip1. In contrast, CDK8/18 inhibition did not have the same effect in KU812 CML cells that do not undergo G1 arrest and are hypersensitive to imatinib. Our results suggest that inhibition of CDK8/19 may be used as a new strategy to prevent quiescence-mediated resistance to BCR-ABL inhibitors. ### Competing Interest Statement IBR is Founder and President and EVB and MC are consultants of Senex Biotechnology, Inc. Other authors declare no conflict of interest. * ### List of abbreviations BCR-ABLi : BCR-ABL inhibitor(s) CDK : cyclin-dependent kinase CDK8/19i : CDK8/19 inhibitor(s) CKI : cyclin-dependent kinase inhibitor CML : chronic myelogenous leukemia Das : dasatinib DEG : differentially expressed genes Dox : doxycycline IM : imatinib mesylate LSC : leukemia stem cells Nilo : nilotinib PARP : poly (ADP-ribose) polymerase SenB : senexin B.