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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

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.

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Published In

Cancer Cell

DOI

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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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

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