2. Academic Validation
  3. Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling

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

  • Commun Biol. 2023 Mar 10;6(1):255. doi: 10.1038/s42003-023-04618-3.
David M Walter # 1 2 3,  Amy C Gladstein # 1 2,  Katherine R Doerig 1 2,  Ramakrishnan Natesan 1,  Saravana G Baskaran 1,  A Andrea Gudiel 1,  Keren M Adler 1 2,  Jonuelle O Acosta 1 2,  Douglas C Wallace 4,  Irfan A Asangani 1 2 5,  David M Feldser 6 7 8
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 2 Cell and Molecular Biology Graduate Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 3 Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4 Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 5 Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA.
  • 6 Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. dfeldser@upenn.edu.
  • 7 Cell and Molecular Biology Graduate Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. dfeldser@upenn.edu.
  • 8 Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA. dfeldser@upenn.edu.
  • # Contributed equally.
PMID: 36899051 DOI: 10.1038/s42003-023-04618-3
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.

Figures
Products