학술논문
PGC1α/β Expression Predicts Therapeutic Response to Oxidative Phosphorylation Inhibition in Ovarian Cancer.
Document Type
Academic Journal
Author
Ghilardi C; Laboratory of Cancer Metastasis Therapeutics, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.; Moreira-Barbosa C; Laboratory of Cancer Metastasis Therapeutics, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.; Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.; Brunelli L; Laboratory of Mass Spectrometry, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.; Ostano P; Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia Valenta, Biella, Italy.; Panini N; Laboratory of Anticancer Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.; Lupi M; Laboratory of Anticancer Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.; Anastasia A; Laboratory of Cancer Metastasis Therapeutics, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.; Fiordaliso F; Laboratory of Cardiovascular Clinical Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.; Salio M; Laboratory of Cardiovascular Clinical Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.; Formenti L; Laboratory of Cancer Metastasis Therapeutics, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.; Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.; Russo M; Laboratory of Cancer Metastasis Therapeutics, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.; Arrigoni E; Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.; Chiaradonna F; Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.; Chiorino G; Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia Valenta, Biella, Italy.; Draetta G; Institute for Applied Cancer Science, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, Texas.; TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, Texas.; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.; Marszalek JR; TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, Texas.; Vellano CP; TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, Texas.; Pastorelli R; Laboratory of Mass Spectrometry, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.; Bani M; Laboratory of Cancer Metastasis Therapeutics, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.; Decio A; Laboratory of Cancer Metastasis Therapeutics, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.; Giavazzi R; Laboratory of Cancer Metastasis Therapeutics, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Source
Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE
Subject
Language
English
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.
(©2022 The Authors; Published by the American Association for Cancer Research.)
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.
(©2022 The Authors; Published by the American Association for Cancer Research.)