The sensitivity of acute myeloid leukemia to CDK8/19 inhibitors is determined by their metabolic profile
Varlamova, E. A.; Andreeva, D. V.; Dalina, A. A.; Misnik, E. V.; Pavlenko, N. G.; Bruter, A. V.; Tatarskiy, V. V.
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Cyclin-dependent kinases CDK8/19 are serine/threonine kinases that regulate transcription in both normal and tumor cells. Several studies have demonstrated that inhibition of CDK8/19 leads to selective cell death in acute myeloid leukemia (AML) cells and has antileukemic activity in patients with relapsed or refractory AML with acceptable tolerability. However, the exact mechanism of AML sensitivity to CDK8/19 inhibitors is poorly understood and markers of clinical sensitivity to them are debated. One of the key goals of the current research was to identify the molecular mechanisms underlying this resistance/sensitivity and to discover new markers for selection of sensitive tumors. In this study, we showed that the action of CDK8/19i induces changes in metabolism-related genes, primarily glycolysis, only in CDK8/19 dependent cell lines. We found that sensitivity to CDK8/19i is associated with a more glycolytic metabolic profile of AML cells, which is a combination of cellular respiratory function and the expression of metabolism-associated genes.
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