Lipid rafts, caveolae, and epidermal growth factor receptor family: friends or foes?

Abstract

Lipid rafts are dynamic microdomains enriched with cholesterol and sphingolipids that play critical roles in cellular processes by organizing and concentrating specific proteins involved in signal transduction. The interplay between lipid rafts, raft-associated caveolae and the human epidermal growth factor receptors has significant implications in cancer biology, particularly in breast and gastric cancer therapy resistance. This review examines the structural and functional characteristics of lipid rafts, their involvement in EGFR and HER2 signaling, and the impact of lipid rafts/CXCL12/CXCR4/HER2 axis on bone metastasis. We also discuss the potential of targeting lipid rafts and caveolin-1 to enhance therapeutic strategies against HER2-positive cancers and the impact of co-localization of trastuzumab or antibody drug conjugates with caveolin-1 on therapy response. Emerging evidence suggests that disrupting lipid raft integrity or silencing caveolin-1, through several strategies including cholesterol-lowering molecules, can influence HER2 availability and internalization, enhancing anti-HER2 targeted therapy and offering a novel approach to counteract drug resistance and improve treatment efficacy.

Keywords: Bone metastasis; Caveolin-1; Human epidermal growth factor receptors; Lipid rafts; Target therapy resistance.

Fig. 1

Plasma membrane organization of flat and invaginated lipid rafts Lipid rafts are specialized membrane microdomains enriched with sphingolipids and cholesterol. Flat lipid rafts are small and ordered structures rich in flotillin. Invaginated lipid rafts present an invaginated configuration, called caveolae, rich in caveolins. Several proteins and receptors, such as tyrosine kinases, are associated with rafts (created with BioRender.com)

Fig. 2

Impact of lipid rafts and lipid raft-associated proteins on HER2 expression in the cell membrane. Left panel, colocalization of caveolin-1 and anti-HER2 ADCs can impair HER2 and ADC degradation by the lysosome, reducing therapy response. Middle panel, MAL2 lipid raft-associated protein can cause HER2 retention in the cell membrane. MAL2 inhibition can resensitize to target therapies HER2-positive resistant cells. Right panel, HER2 dissociation by the B subunit of cholera toxin from GM1 raft-associated ganglioside decreases HER2 dimerization and phosphorylation (created with BioRender.com)

Fig. 3

Effect of cholesterol-lowering molecules on lipid raft,caveolin-1 and HER2. Destruction of lipid-raft and inhibition of raft-associated proteins such as caveolin-1 can reduce ErbB receptors recycling, increase their availability in cell membranes, and enhance anti-HER2 mAb and ADCs avidity and efficacy (created by BioRender.com)