Lipidomic adaptation and membrane physical changes underlie tamoxifen resistance in breast cancer: molecular dynamics...

Drug resistance in breast cancer (BC) is strongly linked to plasma membrane lipid remodeling, notably the loss of lipid asymmetry and elevated cholesterol (CHL) and sphingomyelin (SM) levels. We performed multi-scale molecular dynamics (MD) simulations on eight distinct lipid bilayer models-ranging from normal asymmetric (N1, N2) to cancer-mimetic symmetric states (C1-C5)-at all-atom and coarse-grained resolutions to investigate their impact on tamoxifen (TAM) permeation. Unbiased MD and umbrella sampling were used to compute potential of mean force (PMF) profiles. Our results indicate that membrane symmetrization and CHL/SM enrichment synergistically induce lipid condensation, increasing bilayer thickness (D_HH), reducing area per lipid (APL) and lateral fluidity. Crucially, PMF profiles reveal the core resistance mechanism: while TAM permeates freely through base cancer models (C2), drug-resistant CHL/SM-rich membranes (C3, C4) act as severe energetic barriers. These rigid membranes strongly trap the drug within specific hydrophobic regions (energy minima of ∼-38 kJ mol^-1), limiting penetration into the bilayer core. These findings provide a molecular-level understanding of how lipidomic alterations dictate TAM permeability, suggesting that targeting membrane lipid metabolism or designing lipid-modulating adjuvants are promising therapeutic strategies to overcome drug resistance.