4.7 Article

Targeting lipid metabolism is an emerging strategy to enhance the efficacy of anti-HER2 therapies in HER2-positive breast cancer

期刊

CANCER LETTERS
卷 511, 期 -, 页码 77-87

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ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.04.023

关键词

HER2-Positive breast cancer; Anti-HER2 resistance; Metabolic reprogramming; FASN; CD36

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资金

  1. Associazione Italiana per la Ricerca sul Cancro (AIRC) [22977, 22943]
  2. Scientific Directorate of Fondazione IRCCS Istituto Nazionale dei Tumori

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De novo or acquired resistance to currently available HER2 inhibitors in cancer cells poses a challenge in clinical practice. Inhibiting fatty acid biosynthesis and uptake may be a potential strategy to overcome resistance to anti-HER2 therapies in HER2+ breast cancer patients. Ongoing clinical trials are investigating the combination of inhibiting FA metabolism with HER2 inhibitors in this patient population.
De novo or acquired resistance of cancer cells to currently available Human Epidermal Growth Factor Receptor 2 (HER2) inhibitors represents a clinical challenge. Several resistance mechanisms have been identified in recent years, with lipid metabolism reprogramming, a well-established hallmark of cancer, representing the last frontier of preclinical and clinical research in this field. Fatty Acid Synthase (FASN), the key enzyme required for fatty acids (FAs) biosynthesis, is frequently overexpressed/activated in HER2-positive (HER2+) breast cancer (BC), and it crucially sustains HER2+ BC cell growth, proliferation and survival. After the synthesis of new, selective and well tolerated FASN inhibitors, clinical trials have been initiated to test if these compounds are able to re-sensitize cancer cells with acquired resistance to HER2 inhibition. More recently, the upregulation of FA uptake by cancer cells has emerged as a potentially new and targetable mechanism of resistance to anti-HER2 therapies in HER2+ BC, thus opening a new era in the field of targeting metabolic reprogramming in clinical setting. Here, we review the available preclinical and clinical evidence supporting the inhibition of FA biosynthesis and uptake in combination with anti-HER2 therapies in patients with HER2+ BC, and we discuss ongoing clinical trials that are investigating these combination approaches.

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