Glucose-dependent acetylation of Rictor promotes targeted cancer therapy resistance

Significance Cancer cells reprogram their metabolism in response to growth factor receptor mutations. However, the effect of altered nutrient levels on oncogenic signaling and therapeutic response is not well understood. We demonstrate that glucose or acetate, two abundant “fuel” sources in the brain, promote epidermal growth factor receptor vIII (EGFRvIII)-dependent signaling through activation of mechanistic target of rapamycin complex 2 (mTORC2) by acetylation of its core component Rictor. This activity is mediated through elevated levels of acetyl-CoA. A surprising implication of this study is that glucose or acetate can contribute to targeted therapy resistance by maintaining signaling through downstream components of the growth factor receptor signaling cascade. Cancer cells adapt their signaling in response to nutrient availability. To uncover the mechanisms regulating this process and its functional consequences, we interrogated cell lines, mouse tumor models, and clinical samples of glioblastoma (GBM), the highly lethal brain cancer. We discovered that glucose or acetate is required for epidermal growth factor receptor vIII (EGFRvIII), the most common growth factor receptor mutation in GBM, to activate mechanistic target of rapamycin complex 2 (mTORC2) and promote tumor growth. Glucose or acetate promoted growth factor receptor signaling through acetyl-CoA–dependent acetylation of Rictor, a core component of the mTORC2 signaling complex. Remarkably, in the presence of elevated glucose levels, Rictor acetylation is maintained to form an autoactivation loop of mTORC2 even when the upstream components of the growth factor receptor signaling pathway are no longer active, thus rendering GBMs resistant to EGFR-, PI3K (phosphoinositide 3-kinase)-, or AKT (v-akt murine thymoma viral oncogene homolog)-targeted therapies. These results demonstrate that elevated nutrient levels can drive resistance to targeted cancer treatments and nominate mTORC2 as a central node for integrating growth factor signaling with nutrient availability in GBM.

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