Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer.
Patients with germline fumarate hydratase (FH) mutation are predisposed to develop aggressive kidney cancer with few treatment options and poor therapeutic outcomes. Activity of the proto-oncogene ABL1 is upregulated in FH-deficient kidney tumors and drives a metabolic and survival signaling network necessary to cope with impaired mitochondrial function and abnormal accumulation of intracellular fumarate. Excess fumarate indirectly stimulates ABL1 activity, while restoration of wild-type FH abrogates both ABL1 activation and the cytotoxicity caused by ABL1 inhibition or knockdown. ABL1 upregulates aerobic glycolysis via the mTOR/HIF1α pathway and neutralizes fumarate-induced proteotoxic stress by promoting nuclear localization of the antioxidant response transcription factor NRF2. Our findings identify ABL1 as a pharmacologically tractable therapeutic target in glycolytically dependent, oxidatively stressed tumors.
Sourbier, C; Ricketts, CJ; Matsumoto, S; Crooks, DR; Liao, P-J; Mannes, PZ; Yang, Y; Wei, M-H; Srivastava, G; Ghosh, S; Chen, V; Vocke, CD; Merino, M; Srinivasan, R; Krishna, MC; Mitchell, JB; Pendergast, AM; Rouault, TA; Neckers, L; Linehan, WM
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