Open AccessThe Panitumumab EGFR Complex Reveals a Binding Mechanism That Overcomes Cetuximab Induced Resistance
Author(s) -
E. Allen Sickmier,
Robert J. Kurzeja,
Klaus Michelsen,
Mukta Vazir,
Evelyn Yang,
Andrew S. Tasker
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0163366
Subject(s) - panitumumab , cetuximab , epidermal growth factor receptor , colorectal cancer , ectodomain , medicine , cancer research , point mutation , egfr inhibitors , mutation , oncology , biology , cancer , receptor , genetics , gene
Panitumumab and cetuximab target the epidermal growth factor receptor for 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 mutation in the ectodomain of EGFR (S468R) confers acquired or secondary resistance in cetuximab treated patients, which is not observed in panitumumab-treated patients. Structural and biophysical studies presented here show this mutation directly blocks cetuximab binding to EGFR domain III and describes a unique mechanism by which panitumumab uses a central cavity to accommodate this mutation.