TY - JOUR
T1 - PGC1α/β Expression Predicts Therapeutic Response to Oxidative Phosphorylation Inhibition in Ovarian Cancer
AU - Ghilardi, Carmen
AU - Moreira-Barbosa, Catarina
AU - Brunelli, Laura
AU - Ostano, Paola
AU - Panini, Nicoló
AU - Lupi, Monica
AU - Anastasia, Alessia
AU - Fiordaliso, Fabio
AU - Salio, Monica
AU - Formenti, Laura
AU - Russo, Massimo
AU - Arrigoni, Edoardo
AU - Chiaradonna, Ferdinando
AU - Chiorino, Giovanna
AU - Draetta, Giulio
AU - Marszalek, Joseph R.
AU - Vellano, Christopher P.
AU - Pastorelli, Roberta
AU - Bani, Maria Rosa
AU - Decio, Alessandra
AU - Giavazzi, Raffaella
N1 - Publisher Copyright:
© 2022 The Authors.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-21-1223
DO - 10.1158/0008-5472.CAN-21-1223
M3 - Article
C2 - 35131872
AN - SCOPUS:85128458247
SN - 0008-5472
VL - 82
SP - 1423
EP - 1434
JO - Cancer Research
JF - Cancer Research
IS - 7
ER -