The Panitumumab EGFR Complex Reveals a Binding Mechanism That Overcomes Cetuximab Induced Resistance.

Panitumumaband cetuximabtarget the epidermal growth factor receptorfor the treatment of metastatic colorectal cancer. These therapies provide a significant survival benefit to patients with metastatic colorectal cancer with wild-type RAS. A single point mutationin the ectodomainof EGFR (S468R) confers acquired or secondary resistance in cetuximabtreated patients, which is not observed in panitumumab-treated patients. Structural and biophysicalstudies presented here show this mutation directly blocks cetuximabbinding to EGFR domain III and describes a unique mechanism by which panitumumabuses a central cavity to accommodate this mutation.