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Synthetic lethality of combined glutaminase and Hsp90 inhibition in mTORC1-driven tumor cells. | LitMetric

Synthetic lethality of combined glutaminase and Hsp90 inhibition in mTORC1-driven tumor cells.

Proc Natl Acad Sci U S A

Department of Cell Biology, Harvard Medical School, Boston, MA 02115; Sandra and Edward Meyer Cancer Center, Department of Pharmacology, Weill Cornell Medical College, New York, NY 10021

Published: January 2015

AI Article Synopsis

Article Abstract

The mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals from growth factors, nutrients, and cellular energy status to control a wide range of metabolic processes, including mRNA biogenesis; protein, nucleotide, and lipid synthesis; and autophagy. Deregulation of the mTORC1 pathway is found in cancer as well as genetic disorders such as tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyomatosis. Recent studies have shown that the mTORC1 inhibitor rapamycin and its analogs generally suppress proliferation rather than induce apoptosis. Therefore, it is critical to use alternative strategies to induce death of cells with activated mTORC1. In this study, a small-molecule screen has revealed that the combination of glutaminase (GLS) and heat shock protein 90 (Hsp90) inhibitors selectively triggers death of TSC2-deficient cells. At a mechanistic level, high mTORC1-driven translation rates in TSC1/2-deficient cells, unlike wild-type cells, sensitizes these cells to endoplasmic reticulum (ER) stress. Thus, Hsp90 inhibition drives accumulation of unfolded protein and ER stress. When combining proteotoxic stress with oxidative stress by depletion of the intracellular antioxidant glutathione by GLS inhibition, acute cell death is observed in cells with activated mTORC1 signaling. This study suggests that this combination strategy may have the potential to be developed into a therapeutic use for the treatment of mTORC1-driven tumors.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291663PMC
http://dx.doi.org/10.1073/pnas.1417015112DOI Listing

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