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.
Computational Biophysics Laboratory (GRIB-IMIM), Universitat Pompeu Fabra , Barcelona Biomedical Research Park (PRBB), C/Doctor Aiguader 88, 08003 Barcelona, Spain.
Ignasi
I
Buch
Noelia
N
Ferruz
Gianni
G
De Fabritiis
D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004815:Epidermal Growth Factor / Q000737:chemistry; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D009154:Mutation; D020890:Neuregulin-1 / Q000737:chemistry; D061905:Single-Domain Antibodies / Q000737:chemistry*; D013816:Thermodynamics; D016211:Transforming Growth Factor alpha / Q000737:chemistry
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D008024:Ligands; D020890:Neuregulin-1; D061905:Single-Domain Antibodies; D016211:Transforming Growth Factor alpha; C117463:heregulin alpha; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab