TY - JOUR T1 - Data-driven discovery of targets for bipotent anticancer drugs identifies Estrogen Related Receptor Alpha JF - bioRxiv DO - 10.1101/2021.10.25.465724 SP - 2021.10.25.465724 AU - Avinash D. Sahu AU - Xiaoman Wang AU - Phillip Munson AU - Jan Klomp AU - Xiaoqing Wang AU - Shengqing Gu AU - Gege Qian AU - Phillip Nicol AU - Zexian Zeng AU - Chenfei Wang AU - Collin Tokheim AU - Wubing Zhang AU - Jingxin Fu AU - Jin Wang AU - Nishanth U. Nair AU - Joost Rens AU - Meriem Bourajjaj AU - Bas Jansen AU - Inge Leenders AU - Jaap Lemmers AU - Mark Musters AU - Sanne van Zanten AU - Laura van Zelst AU - Jenny Worthington AU - Myles Brown AU - Jun S. Liu AU - Dejan Juric AU - Cliff A. Meyer AU - Arthur Oubrie AU - X. Shirley Liu AU - David E. Fisher AU - Keith T. Flaherty Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/10/26/2021.10.25.465724.abstract N2 - Drugs that kill tumors through multiple mechanisms have potential for broad clinical benefits, with a reduced propensity to resistance. We developed BipotentR, a computational approach to find cancer-cell-specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway. Using tumor metabolism as proof-of-principle, BipotentR identified 38 candidate immune-metabolic regulators by combining epigenomes with bulk and single-cell tumor transcriptomes from patients. Inhibition of top candidate ESRRA (Estrogen Related Receptor Alpha) killed tumors by direct effects on energy metabolism and two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization (ii) antigen-presentation stimulation, recruiting CD8+T cells into tumors. ESRRA is activated in immune-suppressive and immunotherapy-resistant tumors of many types, suggesting broad clinical relevance. We also applied BipotentR to angiogenesis and growth-suppressor pathways, demonstrating a widely applicable approach to identify drug targets that act simultaneously through multiple mechanisms. BipotentR is publicly available at http://bipotentr.dfci.harvard.edu/.One-Sentence Summary BipotentR identifies targets for bipotent anticancer drugs, as shown by the energy and immune effects of ESRRA inhibition.Competing Interest StatementThe authors have declared no competing interest. ER -