Targeting Fatty Acid Oxidation Enhances Response to HER2-targeted Therapy

Metabolic reprogramming is a hallmark of tumorigenesis and includes alterations in glucose and fatty acid metabolism. In this study, we investigated the role of Carnitine palmitoyl transferase 1A (CPT1A), a key enzyme in fatty acid oxidation (FAO), in the induction of HER2+ (Human Epidermal growth factor 2, ErbB2) breast cancer. Using an ErbB2+ genetically engineered mouse models, we found that ablation of CPT1A delayed tumor onset and reduced tumor growth, angiogenesis, and metastatic capacity. CPT1A-deficient ErbB2+ cells exhibited impaired mitochondrial function, leading to a reliance on the tricarboxylic acid cycle to reduce NAD+/FAD for energy production. Consequently, loss of CPT1A resulted in glucose dependency and an inability to metabolize fats. CPT1A-deficient ErbB2+ tumor cells exhibited increased oxidative stress and upregulated nuclear factor erythroid 2-related factor 2 (NRF2) activity. Inhibiting NRF2 or silencing its expression reduced proliferation and glucose consumption in CPT1A-deficient cells. In pre-clinical models of ErbB2+ breast cancer, combining a ketogenic diet with an anti-ErbB2 monoclonal antibody in the context of CPT1A deficiency significantly reduced tumor growth and increased survival. Furthermore, combining the ketogenic diet with CPT1A ablation suppressed tumor growth, enhanced apoptosis, and reduced lung metastasis. Additionally, using an immunocompetent model, we provide evidence that CPT1A inhibition attenuated tumor growth and proliferation by promoting an antitumor immune microenvironment that enhanced the efficacy of ErbB2 targeted therapy. These findings provide insight into the metabolic rewiring in HER2+ breast cancer and highlight the potential of targeting fatty acid oxidation and employing metabolic interventions as a combination therapy strategy for HER2+ breast cancer patients, including those resistant to standard treatment regimes. Overall design: Mammary epithelial cells from transgenic model of breast cancer (MMTV-Neu NDL 2.5-IRES-CRE) were used to study the effects of CPT1A deletion on HER2-driven tumorigenesis. Transcriptomic analysis (RNA-Seq) was performed on cell line preparations from n = two (NIC/wild-type) and n = 4 (NIC/conditional Cpt1a KO) independent tumor-derived cell lines per genotype,