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

Publication ,  Journal Article
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 ...
Published in: Cancer Cell
December 8, 2014
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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.

Duke Scholars

Ann Marie Pendergast
Author Ann Marie Pendergast Pharmacology & Cancer Biology
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Published In

Cancer Cell

DOI

10.1016/j.ccell.2014.10.005

EISSN

1878-3686

Publication Date

December 8, 2014

Volume

26

Issue

6

Start / End Page

840 / 850

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Signal Transduction
  • Quinazolines
  • Proto-Oncogene Proteins c-abl
  • Proto-Oncogene Mas
  • Piperidines
  • Oxidative Stress
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • NF-E2-Related Factor 2
 

Citation

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Chicago
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Sourbier, C., Ricketts, C. J., Matsumoto, S., Crooks, D. R., Liao, P.-J., Mannes, P. Z., … Linehan, W. M. (2014). Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer. Cancer Cell, 26(6), 840–850. https://doi.org/10.1016/j.ccell.2014.10.005
Sourbier, Carole, Christopher J. Ricketts, Shingo Matsumoto, Daniel R. Crooks, Pei-Jyun Liao, Philip Z. Mannes, Youfeng Yang, et al. “Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer.” Cancer Cell 26, no. 6 (December 8, 2014): 840–50. https://doi.org/10.1016/j.ccell.2014.10.005.
Sourbier C, Ricketts CJ, Matsumoto S, Crooks DR, Liao P-J, Mannes PZ, et al. Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer. Cancer Cell. 2014 Dec 8;26(6):840–50.
Sourbier, Carole, et al. “Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer.” Cancer Cell, vol. 26, no. 6, Dec. 2014, pp. 840–50. Pubmed, doi:10.1016/j.ccell.2014.10.005.
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. Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer. Cancer Cell. 2014 Dec 8;26(6):840–850.
Journal cover image

Published In

Cancer Cell

DOI

10.1016/j.ccell.2014.10.005

EISSN

1878-3686

Publication Date

December 8, 2014

Volume

26

Issue

6

Start / End Page

840 / 850

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Signal Transduction
  • Quinazolines
  • Proto-Oncogene Proteins c-abl
  • Proto-Oncogene Mas
  • Piperidines
  • Oxidative Stress
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • NF-E2-Related Factor 2