Format

Send to

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

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

Author information

1
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
2
Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
3
Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA.
4
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
5
Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Development, Bethesda, MD 20892, USA.
6
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address: wml@nih.gov.

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.

PMID:
25490448
PMCID:
PMC4386283
DOI:
10.1016/j.ccell.2014.10.005
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center