Exploiting mitochondrial and metabolic homeostasis as a vulnerability in NF1 deficient cells
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Robert J. Allaway1, Matthew D. Wood2,8, Sondra L. Downey2, Stephanie J. Bouley1, Nicole A. Traphagen1, Jason D. Wells3, Jaya Batra2,9, Sir Norman Melancon2,10, Carol Ringelberg1,4, William Seibel5, Nancy Ratner6 and Yolanda Sanchez1,7
1Department of Molecular and Systems Biology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA
2Department of Pharmacology and Toxicology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA
3Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA
4Bioinformatics Shared Resource, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA
5Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, OH 45229, USA
6Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, OH 45229, USA
7Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA
8Current address: Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA
9Current address: Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
10Current address: Vanderbilt School of Medicine, Nashville, TN 37232, USA
Yolanda Sanchez, email: email@example.com
Keywords: neurofibromin 1; RAS; synthetic lethal; mitochondria; proteostasis
Received: October 19, 2016 Accepted: July 09, 2017 Epub: July 18, 2017 Published: March 23, 2018
Neurofibromatosis type 1 is a disease caused by mutation of neurofibromin 1 (NF1), loss of which results in hyperactive Ras signaling and a concomitant increase in cell proliferation and survival. Patients with neurofibromatosis type 1 frequently develop tumors such as plexiform neurofibromas and malignant peripheral nerve sheath tumors. Mutation of NF1 or loss of the NF1 protein is also observed in glioblastoma, lung adenocarcinoma, and ovarian cancer among other sporadic cancers. A therapy that selectively targets NF1 deficient tumors would substantially advance our ability to treat these malignancies.
To address the need for these therapeutics, we developed and conducted a synthetic lethality screen to discover molecules that target yeast lacking the homolog of NF1, IRA2. One of the lead candidates that was observed to be synthetic lethal with ira2Δ yeast is Y100. Here, we describe the mechanisms by which Y100 targets ira2Δ yeast and NF1-deficient tumor cells. Y100 treatment disrupted proteostasis, metabolic homeostasis, and induced the formation of mitochondrial superoxide in NF1-deficient cancer cells. Previous studies also indicate that NF1/Ras-dysregulated tumors may be sensitive to modulators of oxidative and ER stress. We hypothesize that the use of Y100 and molecules with related mechanisms of action represent a feasible therapeutic strategy for targeting NF1 deficient cells.
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