PGC1α/β Expression Predicts Therapeutic Response to Oxidative Phosphorylation Inhibition in Ovarian Cancer

Authors

Carmen Ghilardi
Catarina Moreira-Barbosa
Laura Brunelli
Paola Ostano
Nicolò Panini
Monica Lupi
Alessia Anastasia
Fabio Fiordaliso
Monica Salio
Laura Formenti
Massimo Russo
Edoardo Arrigoni
Ferdinando Chiaradonna
Giovanna Chiorino
Giulio Draetta
Joseph R Marszalek
Christopher P Vellano
Roberta Pastorelli
MariaRosa Bani
Alessandra Decio
Raffaella Giavazzi

Publication Date

4-1-2022

Journal

Cancer Research

Abstract

Ovarian cancer is the deadliest gynecologic cancer, and novel therapeutic options are crucial to improve overall survival. Here we provide evidence that impairment of oxidative phosphorylation (OXPHOS) can help control ovarian cancer progression, and this benefit correlates with expression of the two mitochondrial master regulators PGC1α and PGC1β. In orthotopic patient-derived ovarian cancer xenografts (OC-PDX), concomitant high expression of PGC1α and PGC1β (PGC1α/β) fostered a unique transcriptional signature, leading to increased mitochondrial abundance, enhanced tricarboxylic acid cycling, and elevated cellular respiration that ultimately conferred vulnerability to OXPHOS inhibition. Treatment with the respiratory chain complex I inhibitor IACS-010759 caused mitochondrial swelling and ATP depletion that consequently delayed malignant progression and prolonged the lifespan of high PGC1α/β-expressing OC-PDX-bearing mice. Conversely, low PGC1α/β OC-PDXs were not affected by IACS-010759, thus pinpointing a selective antitumor effect of OXPHOS inhibition. The clinical relevance of these findings was substantiated by analysis of ovarian cancer patient datasets, which showed that 25% of all cases displayed high PGC1α/β expression along with an activated mitochondrial gene program. This study endorses the use of OXPHOS inhibitors to manage ovarian cancer and identifies the high expression of both PGC1α and β as biomarkers to refine the selection of patients likely to benefit most from this therapy.

Significance: OXPHOS inhibition in ovarian cancer can exploit the metabolic vulnerabilities conferred by high PGC1α/β expression and offers an effective approach to manage patients on the basis of PGC1α/β expression.

Keywords

Animals, Female, Humans, Mice, Mitochondria, Ovarian Neoplasms, Oxidation-Reduction, Oxidative Phosphorylation, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, RNA-Binding Proteins

DOI

10.1158/0008-5472.CAN-21-1223

PMID

35131872

PMCID

PMC9359716

PubMedCentral® Posted Date

2-7-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes