Oxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic...

Area of Science:

• Oncology
• Metabolic pathways
• Cancer research

Background:

• Endocrine therapy and CDK4/6 inhibitor resistance is common in estrogen receptor-positive breast cancer (ER+ BC).
• A subset of metastatic ER+ BC exhibits a strong dependence on oxidative phosphorylation (OXPHOS) for survival and proliferation.

Purpose of the Study:

• To investigate the role of OXPHOS in treatment-resistant ER+ BC.
• To evaluate the efficacy of the OXPHOS inhibitor IACS-010759 in preclinical models of resistant ER+ BC.

Main Methods:

• Genomic and metabolomic analyses of patient tumors, patient-derived xenografts (PDX), and cell lines.
• In vivo efficacy studies of IACS-010759 in endocrine- and palbociclib-resistant PDX models.
• In vitro studies assessing OXPHOS dependency and reactive oxygen species (ROS) levels.

Main Results:

• IACS-010759 significantly inhibited tumor growth in multiple resistant PDX models.
• Mutations in PIK3CA/AKT1 genes were associated with response to IACS-010759.
• High expression of OXPHOS-associated genes in ER+ BC patients predicts poor prognosis.

Conclusions:

• Oxidative phosphorylation (OXPHOS) is a critical vulnerability in a fraction of treatment-resistant ER+ BC.
• Targeting OXPHOS with inhibitors like IACS-010759 shows promise for overcoming resistance.
• OXPHOS dependency and associated gene expression may serve as predictive biomarkers for treatment response.