Targeting Glutaminase May Overcome Resistance to mTOR Inhibition

Lung squamous cell carcinoma (SCC) is characterized by increased glucose metabolism that fuels rapid tumor growth. These tumors often develop resistance to conventional chemotherapy as well as immune checkpoint inhibitors. Thus, there is an urgent need to identify druggable targets. The Cancer Genome Atlas revealed frequent alterations in receptor tyrosine kinases that result in activation of mTOR signaling, but single-agent PI3K/AKT/mTOR inhibitors have limited efficacy. mTOR inhibition suppresses glucose metabolism in SCC, but fails to suppress tumor growth, suggesting that alternative nutrients may circumvent the suppression of glycolysis. Momcilovic and colleagues performed metabolic profiling of lung SCCs in vivo to identify the molecular mechanisms by which they can overcome suppression of glycolysis following chronic mTOR inhibition. In a mouse model of lung SCC, tumors exhibited a high influx of both glucose and glutamine, and mTOR inhibition with MLN128 suppressed glycolysis without slowing tumor growth. However, MLN128 treatment increased glutaminolysis, suggesting that adaptive glutamine metabolism may compensate for the reduction in glycolysis. Mechanistically, MLN128 treatment resulted in a compensatory increase in AKT signaling and inactivation of the downstream substrate GSK3α/β, which normally facilitates degradation of cMYC and cJUN. This led to an upregulation of cMYC and cJUN, which regulate expression of glutaminase (GLS; the enzyme that converts glutamine to glutamate), to drive adaptive glutamine metabolism. GSK3α/β activity was associated with response to single-agent MLN128 in mouse xenografts and patient-derived xenografts (PDX). Strong GSK3α/β phosphorylation (marking inactivation) occurred in nonresponders and weak GSK3α/β phosphorylation occurred in responders, suggesting that GSK3α/β phosphorylation may serve as a predictive biomarker of response. In MLN128-resistant lung SCC xenografts and PDXs, the GLS inhibitor CB-839 resensitized tumors to mTOR inhibition, with combination therapy suppressing tumor growth more effectively than either single agent. Collectively, these findings demonstrate that compensatory glutamine metabolism can promote resistance to mTOR inhibition in lung SCC and suggest that concordant GLS inhibition may overcome resistance.

Momcilovic M, Bailey ST, Lee JT, Fishbein MC, Braas D, Go J, et al. The GSK3 signaling axis regulates adaptive glutamine metabolism in lung squamous cell carcinoma. Cancer Cell 2018;33:905–21.

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