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

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.glutaminase | Hsp90 | mTORC1 | synthetic lethality | inhibitors

Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers

“…Recently, GLS1 inhibitor BPTES or CB-839 was reported to synergize with HSP90 inhibition in mTORC1-driven tumor cells (35), β-lapachone in pancreatic cancer (52), or BCL-2 inhibition in acute myeloid leukemia (53). Here we show that PARP inhibitors exert a synergistic effect in cell growth suppression when combined with GLS1 inhibitors.…”

“…In addition to being a source for de novo nucleoside synthesis, glutamine carbons are utilized for GSH biosynthesis. GSH is synthesized through the conjugation of cysteine, glycine, and glutamate, which is generated from glutamine by GLS1, and contributes to redox homeostasis (35). We hypothesized that glutamine deprivation would impair GSH biosynthesis and enhance intracellular ROS.…”

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

“…HSP90 inhibition Consistent with a role of GLS in controlling ROS and ER stress, HSP90 and GLS inhibition cause ER stress-induced cell death via ROS 253 .…”

MYC, Metabolism, and Cancer

“…Given the extent to which cancer cells rewire metabolism, it stands to reason that combination therapy would be the most promising metabolic inhibition strategy in the clinic. For example, combination strategies, such as PI3K and MYC inhibition for breast cancer, BRAF and mitochondrial Complex I inhibition (phenformin) for melanoma, BRAF and pyruvate dehydrogenase inhibition for melanoma, mTOR and glutaminase inhibition for glioblastoma, and HSP90 and glutaminase inhibition for mTOR activated cancer, appear to have profound preclinical impact on tumorigenesis (220–223). This exciting area of cancer metabolism research has generated deeper and richer understanding of the relationships between oncogenic drivers and metabolism that will guide the field toward successful clinical applications of basic discoveries.…”