Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling

Walter, D. M.; Gladstein, A. C.; Doerig, K. R.; Natesan, R.; Baskaran, S. G.; Gudiel, A. A.; Adler, K. M.; Acosta, J. O.; Wallace, D. C.; Asangani, I. A.; Feldser, D. M.

doi:10.1101/2022.10.06.511146

bioRxiv · 10.1101/2022.10.06.511146

Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling

Walter, D. M.·Gladstein, A. C.·Doerig, K. R.·Natesan, R.·Baskaran, S. G.·Gudiel, A. A.·Adler, K. M.·Acosta, J. O.·Wallace, D. C.·Asangani, I. A.·Feldser, D. M.

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Abstract

SETD2 is a tumor suppressor that is frequently inactivated in several cancer types. The mechanisms through which SETD2 inactivation promotes cancer are unclear, and whether targetable vulnerabilities exist in these tumors is unknown. Here we identify heightened mTORC1-associated gene expression programs and functionally higher levels of oxidative metabolism and protein synthesis as prominent consequences of Setd2 inactivation in KRAS-driven mouse models of lung adenocarcinoma. Blocking oxidative respiration and mTORC1 signaling abrogates the high rates of tumor cell proliferation and tumor growth specifically in SETD2-deficient tumors. Our data nominate SETD2 deficiency as a functional marker of sensitivity to clinically actionable therapeutics targeting oxidative respiration and mTORC1 signaling.

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Walter, D. M., Gladstein, A. C., Doerig, K. R., Natesan, R., Baskaran, S. G., Gudiel, A. A., Adler, K. M., Acosta, J. O., Wallace, D. C., Asangani, I. A., Feldser, D. M.. 2022-10-06. Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling. https://doi.org/10.1101/2022.10.06.511146

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