Computational modeling of an epidermal growth factor receptor single-mutation resistance to cetuximab in colorectal cancer treatment.

Extracellular S468R mutation of the epidermal growth factor receptor (EGFR) was recently identified as the cause of resistance to cetuximab, a widely used drug in colorectal cancer treatment. Here, we have determined the binding free energies of cetuximab's Fab V(H)-V(L) domains and endogenous EGF ligand to wild type and S468R EGFR by high-throughput molecular dynamics. This work provides a possible mechanism of resistance in terms of increased competition, an hypothesis that can be further validated experimentally.