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NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer

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Metabolic reprogramming, which leads to effects such as a higher oxygen consumption rate (OCR) and altered glutamine and glucose metabolism in cells, contributes to the cells resistance to venetoclax and ibrutinib ( CB-839 (Telaglenastat), a potent, reversible, and selective small-molecule inhibitor that targets GLS-1 and has a half-maximal inhibitory concentration (IC 50 ) of 24 nM for recombinant human glutaminase C, has been investigated in solid tumors and in AML, diffuse large B-cell lymphoma, and multiple myeloma cells alone or in combination with other anticancer drugs ( in vitro decreased the concentration of downstream glutaminase metabolites (glutamate, -ketoglutarate, aspartate, fumarate, and malate) and induced cell death ( We hypothesize, that dysregulation of glutaminolysis using CB-839 may overcome drug resistance in CLL cells and be an effective treatment strategy when used alone or in combination with agents that inhibit pathways responsible for survival, proliferation, and migration of CLL lymphocytes