AI Article Synopsis

  • Neurofibromatosis type 1 results from a mutation in the neurofibromin 1 gene, leading to excessive Ras signaling, increased cell growth, and the formation of tumors, including plexiform neurofibromas and malignant peripheral nerve sheath tumors.
  • This mutation also appears in various cancers like glioblastoma, lung adenocarcinoma, and ovarian cancer, indicating a need for targeted therapies that can specifically treat NF1-deficient tumors.
  • The study introduces Y100, a compound identified through a synthetic lethality screen, which disrupts metabolic and proteostasis balance and increases mitochondrial stress in NF1-deficient cancer cells, suggesting it could be a promising treatment strategy for these tumors.

Article Abstract

Neurofibromatosis type 1 is a disease caused by mutation of neurofibromin 1 (), 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 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 , . One of the lead candidates that was observed to be synthetic lethal with yeast is Y100. Here, we describe the mechanisms by which Y100 targets 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882303PMC
http://dx.doi.org/10.18632/oncotarget.19335DOI Listing

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