1. Academic Validation
  2. Targeting fatty acid oxidation enhances response to HER2-targeted therapy

Targeting fatty acid oxidation enhances response to HER2-targeted therapy

  • Nat Commun. 2024 Aug 3;15(1):6587. doi: 10.1038/s41467-024-50998-3.
Ipshita Nandi 1 2 Linjia Ji 1 Harvey W Smith 1 Daina Avizonis 1 Vasilios Papavasiliou 1 2 Cynthia Lavoie 1 Alain Pacis 1 3 Sherif Attalla 1 2 Virginie Sanguin-Gendreau 1 2 William J Muller 4 5
Affiliations

Affiliations

  • 1 Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC, Canada.
  • 2 Department of Biochemistry, McGill University, Montreal, QC, Canada.
  • 3 Canadian Centre for Computational Genomics, McGill University, Montreal, QC, Canada.
  • 4 Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC, Canada. william.muller@mcgill.ca.
  • 5 Department of Biochemistry, McGill University, Montreal, QC, Canada. william.muller@mcgill.ca.
Abstract

Metabolic reprogramming, a hallmark of tumorigenesis, involves alterations in glucose and fatty acid metabolism. Here, we investigate the role of Carnitine palmitoyl transferase 1a (Cpt1a), a key Enzyme in long-chain fatty acid (LCFA) oxidation, in ErbB2-driven breast cancers. In ErbB2+ Breast Cancer Models, ablation of Cpt1a delays tumor onset, growth, and metastasis. However, Cpt1a-deficient cells exhibit increased glucose dependency that enables survival and eventual tumor progression. Consequently, these cells exhibit heightened oxidative stress and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Inhibiting Nrf2 or silencing its expression reduces proliferation and glucose consumption in Cpt1a-deficient cells. Combining the ketogenic diet, composed of LCFAs, or an anti-ErbB2 monoclonal antibody (mAb) with Cpt1a deficiency significantly perturbs tumor growth, enhances Apoptosis, and reduces lung metastasis. Using an immunocompetent model, we show that Cpt1a inhibition promotes an antitumor immune microenvironment, thereby enhancing the efficacy of anti-ErbB2 mAbs. Our findings underscore the importance of targeting fatty acid oxidation alongside HER2-targeted therapies to combat resistance in HER2+ breast Cancer patients.

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