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 PGC1a and PGC1β. In orthotopic patientderived ovarian cancer xenografts (OC-PDX), concomitant high expression of PGC1a 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 PGC1a and b as biomarkers to refine the selection of patients likely to benefit most from this therapy.

Ghilardi, C., Moreira Barbosa, C., Brunelli, L., Ostano, P., Panini, N., Lupi, M., et al. (2022). PGC1α/β Expression Predicts Therapeutic Response to Oxidative Phosphorylation Inhibition in Ovarian Cancer. CANCER RESEARCH, 82(7), 1423-1434 [10.1158/0008-5472.CAN-21-1223].

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

Chiaradonna, Ferdinando;Pastorelli, Roberta;
2022

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 PGC1a and PGC1β. In orthotopic patientderived ovarian cancer xenografts (OC-PDX), concomitant high expression of PGC1a 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 PGC1a and b as biomarkers to refine the selection of patients likely to benefit most from this therapy.
Articolo in rivista - Articolo scientifico
Ovarian cancer, xenograft models, oxphos inhibition, predictive biomarkers, pharmacological response;
English
1423
1434
12
Ghilardi, C., Moreira Barbosa, C., Brunelli, L., Ostano, P., Panini, N., Lupi, M., et al. (2022). PGC1α/β Expression Predicts Therapeutic Response to Oxidative Phosphorylation Inhibition in Ovarian Cancer. CANCER RESEARCH, 82(7), 1423-1434 [10.1158/0008-5472.CAN-21-1223].
Ghilardi, C; Moreira Barbosa, C; Brunelli, L; Ostano, P; Panini, N; Lupi, M; Anastasia, A; Fiordaliso, F; Salio, M; Formenti, L; Russo, M; Arrigoni, E; Chiaradonna, F; Chiorino, G; Draetta, G; Marszalek, J; Vellano, C; Pastorelli, R; Bani, M; Decio, A; Giavazzi, R
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/359273
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