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

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.

• Authors: Carole Sourbier, Christopher J Ricketts, Shingo Matsumoto, Daniel R Crooks, Pei-Jyun Liao, Philip Z Mannes, Youfeng Yang, Ming-Hui Wei, Gaurav Srivastava, Sanchari Ghosh, Viola Chen, Cathy D Vocke, Maria Merino, Ramaprasad Srinivasan, Murali C Krishna, James B Mitchell, Ann Marie Pendergast, Tracey A Rouault, Len Neckers, W Marston Linehan
• Journal: Cancer cell (Cancer Cell) Vol. 26 Issue 6 Pg. 840-850 (Dec 08 2014) ISSN: 1878-3686 [Electronic] United States
• PMID: 25490448 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Fumarates
• MAS1 protein, human
• NF-E2-Related Factor 2
• Piperidines
• Proto-Oncogene Mas
• Quinazolines
• Proto-Oncogene Proteins c-abl
• Fumarate Hydratase
• vandetanib

Topics

• 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, pathology)
• Mice
• NF-E2-Related Factor 2 (genetics, metabolism)
• Neoplasms, Experimental
• Oxidative Stress (drug effects)
• Piperidines (pharmacology)
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-abl (genetics, metabolism)
• Quinazolines (pharmacology)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays