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.
Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Animals , Mice , Adenocarcinoma of Lung/genetics , Genes, Tumor Suppressor , Lung Neoplasms/genetics , Mechanistic Target of Rapamycin Complex 1/genetics , Oxidative Stress , Histone-Lysine N-Methyltransferase/geneticsABSTRACT
The Dockeye software is designed to complement automated docking protocols by allowing the user's chemical know-how and experience of what makes for good protein-ligand binding, knowledge that is not easily encoded into automated algorithms, to guide the docking. It allows the interactive manipulation of the ligand placement against a protein target. Real-time intuitively comprehensible feedback about the location, spatial density, and the extent of both favorable and unfavorable atomic interactions between ligand and protein is provided through a carefully designed graphical object. It is also a tool for the graphical analysis of the interactions of known protein-ligand complexes. Comparative docking of 58 protein-ligand complexes with Dockeye and Autodock Vina shows how this software can be used synergistically with automated docking programs to significantly improve the task of discovery of ligand placement.