title: 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.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Carole
authors.initials: C
authors.lastname: Sourbier
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ricketts
authors.affiliation: Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Crooks
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Pei-Jyun
authors.initials: PJ
authors.lastname: Liao
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Philip Z
authors.initials: PZ
authors.lastname: Mannes
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Youfeng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Wei
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Srivastava
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Sanchari
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Viola
authors.initials: V
authors.lastname: Chen
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Cathy D
authors.initials: CD
authors.lastname: Vocke
authors.affiliation: Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Merino
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Ramaprasad
authors.initials: R
authors.lastname: Srinivasan
authors.affiliation: Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Murali C
authors.initials: MC
authors.lastname: Krishna
authors.affiliation: Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Pendergast
authors.affiliation: Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Development, Bethesda, MD 20892, USA.
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Rouault
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address: wml@nih.gov.
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D005649:Fumarate Hydratase / Q000172:deficiency*; D005650:Fumarates / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009374:Neoplasms, Experimental; D018384:Oxidative Stress / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D005650:Fumarates; C000715470:MAS1 protein, human; D051267:NF-E2-Related Factor 2; D010880:Piperidines; D000090063:Proto-Oncogene Mas; D011799:Quinazolines; D016315:Proto-Oncogene Proteins c-abl; D005649:Fumarate Hydratase; C452423:vandetanib