Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer.


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • December 8, 2014

Published In

Volume / Issue

  • 26 / 6

Start / End Page

  • 840 - 850

PubMed ID

  • 25490448

Pubmed Central ID

  • 25490448

Electronic International Standard Serial Number (EISSN)

  • 1878-3686

Digital Object Identifier (DOI)

  • 10.1016/j.ccell.2014.10.005


  • eng

Conference Location

  • United States