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 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.

• Authors: Jing Li, Alfredo Csibi, Sun Yang, Gregory R Hoffman, Chenggang Li, Erik Zhang, Jane J Yu, John Blenis
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 1 Pg. E21-9 (Jan 06 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 25524627 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Benzoquinones
• HSP90 Heat-Shock Proteins
• Lactams, Macrocyclic
• Multiprotein Complexes
• Small Molecule Libraries
• Sulfides
• TSC2 protein, human
• Thiadiazoles
• Tsc2 protein, mouse
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins
• bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide
• Glutamine
• tanespimycin
• Glutamate Dehydrogenase
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases
• Glutaminase
• Sirolimus

Topics

• Animals
• Apoptosis (drug effects)
• Benzoquinones (pharmacology)
• Cell Line, Tumor
• Cell Shape (drug effects)
• Cell Survival (drug effects)
• Glutamate Dehydrogenase (antagonists & inhibitors, metabolism)
• Glutaminase (antagonists & inhibitors, metabolism)
• Glutamine (metabolism)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Lactams, Macrocyclic (pharmacology)
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Models, Biological
• Multiprotein Complexes (metabolism)
• Oxidation-Reduction (drug effects)
• Phenotype
• Sirolimus (pharmacology)
• Small Molecule Libraries (pharmacology)
• Sulfides (pharmacology)
• TOR Serine-Threonine Kinases (metabolism)
• Thiadiazoles (pharmacology)
• Tuberous Sclerosis (metabolism, pathology)
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins (deficiency, metabolism)
• Xenograft Model Antitumor Assays