Targeting ABL1-Mediated Oxidative Stress Adaptation in Fumarate Hydratase-Deficient Cancer
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels le vandetanib exerce une activité cytotoxique dans des tumeurs rénales présentant un déficit en fumarase lié à une mutation constitutionnelle du gène FH
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.
Cancer Cell , résumé, 2013