Oxidative Phosphorylation Is a Metabolic Vulnerability in Chemotherapy-Resistant Triple-Negative Breast Cancer

Area of Science:

• Oncology
• Metabolic Pathways
• Cancer Metabolism

Background:

• Oxidative phosphorylation (OXPHOS) is a critical metabolic pathway implicated in various cancers, including triple-negative breast cancer (TNBC).
• Elevated OXPHOS expression in TNBC correlates with poorer patient outcomes, suggesting it as a potential therapeutic target.

Purpose of the Study:

• To investigate OXPHOS as a metabolic vulnerability in TNBC.
• To evaluate the efficacy of novel OXPHOS inhibitors, such as IACS-10759, alone and in combination with other targeted therapies.

Main Methods:

• Analysis of RNA from TNBC patient biopsies to identify metabolic pathways associated with outcomes.
• Treatment of TNBC patient-derived xenografts (PDX) with IACS-10759.
• In vivo functional genomics screening to identify synthetic lethal targets in combination with IACS-10759.
• In vitro and in vivo validation of drug combinations, including IACS-10759 with palbociclib (a CDK4/6 inhibitor) and cabozantinib (a multikinase inhibitor).

Main Results:

• Higher OXPHOS signature expression was linked to worse outcomes in TNBC patients.
• IACS-10759 demonstrated tumor growth stabilization in TNBC PDX models.
• Sensitive TNBC models exhibited higher mitochondrial gene expression and belonged to the basal-like 1 subtype.
• Combination therapy with IACS-10759 and palbociclib, or IACS-10759 and cabozantinib, showed enhanced antitumor efficacy.

Conclusions:

• TNBC is highly dependent on OXPHOS, presenting a metabolic vulnerability.
• Targeting OXPHOS with novel inhibitors like IACS-10759, particularly in combination regimens, offers a promising therapeutic strategy for TNBC.
• Combination therapies involving OXPHOS inhibition may enhance the effectiveness of existing targeted treatments for TNBC.