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

• Published in: Cancer letters Vol. 511; pp. 77 - 87
• Main Authors: Ligorio, Francesca, Pellegrini, Ilaria, Castagnoli, Lorenzo, Vingiani, Andrea, Lobefaro, Riccardo, Zattarin, Emma, Santamaria, Marzia, Pupa, Serenella M., Pruneri, Giancarlo, de Braud, Filippo, Vernieri, Claudio
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28.07.2021; Elsevier Limited
• Subjects: Anti-HER2 resistance; Antibodies; Antigens; Biosynthesis; Breast cancer; Cancer therapies; CD36; Cell cycle; Cell growth; Cell survival; Chemotherapy; Clinical trials; Endocrine therapy; Epidermal growth factor; ErbB-2 protein; FASN; Fatty acids; Fatty-acid synthase; Gene amplification; HER2-Positive breast cancer; Kinases; Lipid metabolism; Lipids; Metabolic reprogramming; Metabolism; Mutation; Proteins; Signal transduction; Tumors; BC; LXRα and LXRβ; ACSS2; IHC; SCCs; FADS2; PFL; SREBPs; CD36; Anti-HER2 resistance; ADCC; ISH; FABPpm; FATPs; EGCG; ELOVL6; HER2-Positive breast cancer; Metabolic reprogramming; EMT; ACC1; ACLY; TCA; SCD; FASN; ROS; FAT; AMPK; SLC27; FA; HER2
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.04.023

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. •FA biosynthesis and uptake contribute to HER2+ BC cell growth and resistance to anti-HER2 therapies.•FASN inhibitors showed promising results in HER2+ BC, and they are being tested in clinical trials.•FA uptake could represent a new and targetable resistance mechanism to anti-HER2 therapies.