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PGC1α/β Expression Predicts Therapeutic Response to Oxidative Phosphorylation Inhibition in Ovarian Cancer
Carmen Ghilardi1, Catarina Moreira-Barbosa1,2, Laura Brunelli3
1Laboratory of Cancer Metastasis Therapeutics, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
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.
Insights
Targeting oxidative phosphorylation (OXPHOS) shows promise for ovarian cancer treatment. High PGC1α/β expression predicts sensitivity to OXPHOS inhibitors, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Research
Background:
- Ovarian cancer remains a leading cause of gynecologic cancer deaths, necessitating novel therapeutic strategies.
- Oxidative phosphorylation (OXPHOS) plays a critical role in cellular energy production and cancer metabolism.
- PGC1α and PGC1β are key regulators of mitochondrial biogenesis and function.
Purpose of the Study:
- To investigate the role of oxidative phosphorylation (OXPHOS) impairment in controlling ovarian cancer progression.
- To determine the correlation between PGC1α/β expression and sensitivity to OXPHOS inhibition in ovarian cancer.
- To identify potential biomarkers for selecting ovarian cancer patients who may benefit from OXPHOS inhibitor therapy.
Main Methods:
- Utilized orthotopic patient-derived ovarian cancer xenografts (OC-PDX) to model tumor growth and response.
- Administered the respiratory chain complex I inhibitor IACS-010759 to assess therapeutic efficacy.
- Analyzed ovarian cancer patient datasets to evaluate the clinical relevance of PGC1α/β expression and mitochondrial gene programs.
Main Results:
- High co-expression of PGC1α and PGC1β (PGC1α/β) in OC-PDX models led to increased mitochondrial activity and vulnerability to OXPHOS inhibition.
- Treatment with IACS-010759 selectively delayed tumor progression and prolonged survival in high PGC1α/β-expressing OC-PDX models.
- Conversely, low PGC1α/β expression rendered OC-PDX models unresponsive to IACS-010759.
- Analysis of patient data revealed that 25% of ovarian cancers exhibit high PGC1α/β expression and an activated mitochondrial gene program.
Conclusions:
- Impairment of oxidative phosphorylation (OXPHOS) can effectively control ovarian cancer progression.
- High expression of PGC1α and PGC1β serves as a predictive biomarker for response to OXPHOS inhibitors in ovarian cancer.
- OXPHOS inhibitors represent a promising therapeutic avenue for a subset of ovarian cancer patients defined by PGC1α/β expression.
