Discovery of Targets for Immune-Metabolic Antitumor Drugs Identifies Estrogen-Related Receptor Alpha.

ABSTRACT: 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 proi

SUBMITTER: Sahu A 

PROVIDER: S-EPMC9975674 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature