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

Li , Jing and Csibi , Alfred and Yang , Sun and Hoffman, Gregory and Li , Chenggang and Zhang , Erik and Yu , Jane J and Blenis , John (2015) Synthetic lethality of combined glutaminase and Hsp90 inhibition in mTORC1-driven tumor cells. Proceedings of the National Academy of Sciences of the United States of America, 112 (1). E21-E29. ISSN 1091-6490

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 smallmolecule 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.

Item Type: Article
Keywords: Glutaminase Hsp90 Inhibitors mTORC1 Synthetic lethality
Date Deposited: 25 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/23580

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