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

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

doi:10.18632/oncotarget.19335

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.

Highlights

The development of targeted cancer therapeutics enables clinicians to target malignancies with unique oncogenomic characteristics
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
Saccharomyces cerevisiae lacking the Ras suppressor gene IRA2 were exposed to small molecules selected for structural diversity and drug-like properties (Figure 1A) [32]

Summary

Introduction

The development of targeted cancer therapeutics enables clinicians to target malignancies with unique oncogenomic characteristics. Patients with neurofibromatosis type 1 can exhibit a variety of symptoms including café-au-lait spots, learning disabilities, and predisposition to tumors such as optic pathway gliomas, plexiform neurofibromas (PN), and malignant peripheral nerve sheath tumors (MPNSTs) [5, 6]. These tumors generally exhibit biallelic inactivation of NF1 [7]. NF1 can be depleted in tumors by posttranscriptional regulatory mechanisms such as miRNA silencing and degradation of the NF1 protein by the proteasome [14,15,16,17,18] This suggests that a subset of tumors with a wild-type NF1 gene may not express functional NF1 protein

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Conclusion