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

Carole Sourbier1, Christopher J Ricketts1, Shingo Matsumoto2

  • 1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

Cancer Cell
|December 10, 2014
PubMed

Insights

Patients with fumarate hydratase (FH) mutations develop aggressive kidney cancer. Targeting the proto-oncogene ABL1 offers a potential therapeutic strategy for these tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Germline mutations in fumarate hydratase (FH) predispose individuals to aggressive kidney cancer.
  • FH-deficient tumors exhibit upregulated proto-oncogene ABL1 activity, crucial for survival.
  • ABL1 activation is linked to impaired mitochondrial function and fumarate accumulation.

Purpose of the Study:

  • To investigate the role of ABL1 in FH-deficient kidney cancer.
  • To identify ABL1 as a potential therapeutic target.

Main Methods:

  • Analysis of ABL1 activity in FH-deficient kidney tumors.
  • Investigating the metabolic and signaling pathways regulated by ABL1.
  • Assessing the effects of ABL1 inhibition or knockdown.
  • Evaluating the impact of wild-type FH restoration.

Main Results:

  • ABL1 activity is upregulated in FH-deficient kidney tumors.
  • ABL1 promotes aerobic glycolysis via the mTOR/HIF1α pathway.
  • ABL1 mitigates fumarate-induced proteotoxic stress by activating NRF2.
  • Restoring wild-type FH reduces ABL1 activation and ABL1-dependent cytotoxicity.

Conclusions:

  • ABL1 is a key driver of metabolic and survival pathways in FH-deficient kidney cancer.
  • ABL1 represents a pharmacologically tractable target for these aggressive tumors.
  • Targeting ABL1 may be effective in glycolytically dependent, oxidatively stressed tumors.

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