In Cancer discovery ; h5-index 105.0
UNLABELLED : Drugs that kill tumors through multiple mechanisms have the potential for broad clinical benefits. Here, we first developed an in silico multiomics approach (BipotentR) to find cancer cell-specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway and then used it to identify 38 candidate immune-metabolic regulators. We show the tumor activities of these regulators stratify patients with melanoma by their response to anti-PD-1 using machine learning and deep neural approaches, which improve the predictive power of current biomarkers. The topmost identified regulator, ESRRA, is activated in immunotherapy-resistant tumors. Its inhibition killed tumors by suppressing energy metabolism and activating two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization, and (ii) antigen-presentation stimulation, recruiting CD8+ T cells into tumors. We also demonstrate a wide utility of BipotentR by applying it to angiogenesis and growth suppressor evasion pathways. BipotentR (http://bipotentr.dfci.harvard.edu/) provides a resource for evaluating patient response and discovering drug targets that act simultaneously through multiple mechanisms.
SIGNIFICANCE : BipotentR presents resources for evaluating patient response and identifying targets for drugs that can kill tumors through multiple mechanisms concurrently. Inhibition of the topmost candidate target killed tumors by suppressing energy metabolism and effects on two immune mechanisms.
Sahu Avinash, Wang Xiaoman, Munson Phillip, Klomp Jan P G, Wang Xiaoqing, Gu Shengqing Stan, Han Ya, Qian Gege, Nicol Phillip, Zeng Zexian, Wang Chenfei, Tokheim Collin, Zhang Wubing, Fu Jingxin, Wang Jin, Nair Nishanth Ulhas, Rens Joost A P, Bourajjaj Meriem, Jansen Bas, Leenders Inge, Lemmers Jaap, Musters Mark, van Zanten Sanne, van Zelst Laura, Worthington Jenny, Liu Jun S, Juric Dejan, Meyer Clifford A, Oubrie Arthur, Liu X Shirley, Fisher David E, Flaherty Keith T
2023-Feb-06
