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

Cancer Cell. 2014 Dec 8;26(6):840-850. doi: 10.1016/j.ccell.2014.10.005.

Abstract

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Fumarate Hydratase / deficiency*
  • Fumarates / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glycolysis / drug effects
  • HEK293 Cells
  • Humans
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / pathology
  • Mice
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Neoplasms, Experimental
  • Oxidative Stress / drug effects*
  • Piperidines / pharmacology*
  • Proto-Oncogene Proteins c-abl / genetics
  • Proto-Oncogene Proteins c-abl / metabolism*
  • Quinazolines / pharmacology*
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Fumarates
  • NF-E2-Related Factor 2
  • Piperidines
  • Quinazolines
  • Proto-Oncogene Proteins c-abl
  • Fumarate Hydratase
  • N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine