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.

Targeting lipid metabolism is an emerging strategy to enhance the efficacy of anti-HER2 therapies in HER2-positive breast cancer / F. Ligorio, I. Pellegrini, L. Castagnoli, A. Vingiani, R. Lobefaro, E. Zattarin, M. Santamaria, S.M. Pupa, G. Pruneri, F. de Braud, C. Vernieri. - In: CANCER LETTERS. - ISSN 0304-3835. - 511:(2021 Jul 28), pp. 77-87. [10.1016/j.canlet.2021.04.023]

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

F. Ligorio
Primo
;
I. Pellegrini
Secondo
;
A. Vingiani;R. Lobefaro;E. Zattarin;G. Pruneri;F. de Braud;
2021

Abstract

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.
Anti-HER2 resistance; CD36; FASN; HER2-Positive breast cancer; Metabolic reprogramming; Breast Neoplasms; Female; Humans; Lipid Metabolism; Protein Kinase Inhibitors; Receptor, ErbB-2;
Settore MED/06 - Oncologia Medica
28-lug-2021
mag-2021
Article (author)
File in questo prodotto:
File Dimensione Formato  
targeting lipid metabolism.pdf

solo utenti autorizzati

Tipologia: Publisher's version/PDF
Dimensione 2.17 MB
Formato Adobe PDF
2.17 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/909294
Citazioni
  • ???jsp.display-item.citation.pmc??? 17
  • Scopus 23
  • ???jsp.display-item.citation.isi??? 22
social impact