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Targeting Metabolic Co-dependencies to Overcome Therapeutic Resistance in Cancer

Abstract

Oncogenic mutations in cancer reprogram nutrient metabolism to drive tumor growth and survival under environmental stress and drug treatment, but the molecular mechanisms are not well understood. Using an unbiased proteomic screen, we identified mTORC2 as a critical regulator of amino acid metabolism in cancer via phosphorylation of the cystine-glutamate antiporter xCT. mTORC2 phosphorylates serine 26 at the cytosolic N-terminus of xCT, inhibiting its activity when nutrient is abundant to conserve glutamine-derived glutamate for biosynthesis. Genetic inhibition of mTORC2, or pharmacologic mTOR kinase inhibition, promotes glutamate secretion, cystine uptake and incorporation into glutathione. This adaptation renders tumor cells exquisitely sensitive to combined inhibition of glutathione synthesis and mTOR kinase, resulting in massive ferroptotic tumor cell death. These results identified an unanticipated mechanism of amino acid metabolic reprogramming in cancer, revealing a drug-induced metabolic co-dependency as a potentially exploitable therapeutic vulnerability.

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