title: The Panitumumab EGFR Complex Reveals a Binding Mechanism That Overcomes Cetuximab Induced Resistance.
abstract: 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.
authors.affiliation: Depatment of Therapeutic Discovery, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States of America.
authors.forename: E Allen
authors.identifier: http://orcid.org/0000-0002-5595-9257
authors.initials: EA
authors.lastname: Sickmier
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States of America.
authors.forename: Robert J M
authors.initials: RJ
authors.lastname: Kurzeja
authors.affiliation: Depatment of Therapeutic Discovery, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States of America.
authors.forename: Klaus
authors.initials: K
authors.lastname: Michelsen
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States of America.
authors.forename: Mukta
authors.initials: M
authors.lastname: Vazir
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States of America.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Yang
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States of America.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Tasker