ИСТИНА

Targeted drugs marked a new era in cancer treatment, with imatinib mesylate (Gleevec) as the first and the most remarkable example of selective inactivation of Bcr-Abl chimeric tyrosine kinase vital for chronic myelogenous leukemia (CML) cells. However, resistance to Bcr-Abl inhibitors justifies the need for new therapeutic approaches. Resistance mechanisms include Abl mutations and an epigenetic activation of signaling cascades that maintain the malignant phenotypes. We demonstrated that imatinib and the 3d generation Bcr-Abl blocker PF-114 potently killed logarithmically growing K562 cell line (CML) (IC50 = 0.25 µM and 6 nM, respectively). In striking contrast, the efficacy of PF-114 (but not as much of imatinib) dramatically decreased in a dense culture suggesting that irresponsiveness to PF-114 can emerge due to a protective paracrine regulation. Since imatinib is less selective than PF-114, the former drug can evade protective signaling from bystander cells by inhibiting the targets other than Abl. To circumvent this ‘cell cooperation dependent’ resistance we took advantage of CDK8/19 mediated transcriptional reprogramming whose selective inhibition with a non-toxic compound Senexin B (SenB) has been shown to potently sensitize tumor cell lines and murine xenografts to a number of chemotherapeutics. The K562 cells treated with combinations of SenB with imatinib and PF-114 escaped a G1 phase arrest and underwent apoptosis via caspase activation, cleavage of poly(ADPriboso)polymerase and the loss of mitochondrial membrane potential. At least 12 h of exposure to SenB and imatinib/PF-114 was sufficient to initiate death in logarithmic and dense K562 cells (compared to 24 h for imatinib/PF-114 alone) implicating quick transcriptional reprogramming (via CDK8/19 inhibition) into CML cell sensitization to Bcr-Abl inhibitors. This study was supported by the Megagrant (grant no. 14.W03.31.0020 between the Ministry of Science and Education of the Russian Federation and Institute of Gene Biology, Russian Academy of Sciences).