Targeting fatty acid oxidation enhances response to HER2-targeted therapy

Ipshita Nandi, Linjia Ji, Harvey W. Smith, Daina Avizonis, Vasilios Papavasiliou, Cynthia Lavoie, Alain Pacis, Sherif Attalla, Virginie Sanguin-Gendreau and William J. Muller ()
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Ipshita Nandi: McGill University
Linjia Ji: McGill University
Harvey W. Smith: McGill University
Daina Avizonis: McGill University
Vasilios Papavasiliou: McGill University
Cynthia Lavoie: McGill University
Alain Pacis: McGill University
Sherif Attalla: McGill University
Virginie Sanguin-Gendreau: McGill University
William J. Muller: McGill University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50998-3

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