Exploiting mitochondrial and metabolic homeostasis as a vulnerability in NF1 deficient cells

Robert J. Allaway, Matthew D. Wood, Sondra L. Downey, Stephanie J. Bouley, Nicole A. Traphagen, Jason D. Wells, Jaya Batra, Sir Norman Melancon, Carol Ringelberg, William Seibel, Nancy Ratner, Nancy Yolanda Sanchez

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)15860-15875
Number of pages16
JournalOncotarget
Volume9
Issue number22
DOIs
StatePublished - 2018

Keywords

  • Mitochondria
  • Neurofibromin 1
  • Proteostasis
  • RAS
  • Synthetic lethal

ASJC Scopus subject areas

  • Oncology

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    Allaway, R. J., Wood, M. D., Downey, S. L., Bouley, S. J., Traphagen, N. A., Wells, J. D., Batra, J., Melancon, S. N., Ringelberg, C., Seibel, W., Ratner, N., & Sanchez, N. Y. (2018). Exploiting mitochondrial and metabolic homeostasis as a vulnerability in NF1 deficient cells. Oncotarget, 9(22), 15860-15875. https://doi.org/10.18632/oncotarget.19335