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

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)...

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Autores principales: Sickmier, E. Allen, Kurzeja, Robert J. M., Michelsen, Klaus, Vazir, Mukta, Yang, Evelyn, Tasker, Andrew S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Research Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033319/
https://www.ncbi.nlm.nih.gov/pubmed/27658254
http://dx.doi.org/10.1371/journal.pone.0163366
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author Sickmier, E. Allen
Kurzeja, Robert J. M.
Michelsen, Klaus
Vazir, Mukta
Yang, Evelyn
Tasker, Andrew S.
author_facet Sickmier, E. Allen
Kurzeja, Robert J. M.
Michelsen, Klaus
Vazir, Mukta
Yang, Evelyn
Tasker, Andrew S.
author_sort Sickmier, E. Allen
collection PubMed
description 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.
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spelling pubmed-50333192016-10-10 The Panitumumab EGFR Complex Reveals a Binding Mechanism That Overcomes Cetuximab Induced Resistance Sickmier, E. Allen Kurzeja, Robert J. M. Michelsen, Klaus Vazir, Mukta Yang, Evelyn Tasker, Andrew S. PLoS One Research Article 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. Public Library of Science 2016-09-22 /pmc/articles/PMC5033319/ /pubmed/27658254 http://dx.doi.org/10.1371/journal.pone.0163366 Text en © 2016 Sickmier et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Sickmier, E. Allen
Kurzeja, Robert J. M.
Michelsen, Klaus
Vazir, Mukta
Yang, Evelyn
Tasker, Andrew S.
The Panitumumab EGFR Complex Reveals a Binding Mechanism That Overcomes Cetuximab Induced Resistance
title The Panitumumab EGFR Complex Reveals a Binding Mechanism That Overcomes Cetuximab Induced Resistance
title_full The Panitumumab EGFR Complex Reveals a Binding Mechanism That Overcomes Cetuximab Induced Resistance
title_fullStr The Panitumumab EGFR Complex Reveals a Binding Mechanism That Overcomes Cetuximab Induced Resistance
title_full_unstemmed The Panitumumab EGFR Complex Reveals a Binding Mechanism That Overcomes Cetuximab Induced Resistance
title_short The Panitumumab EGFR Complex Reveals a Binding Mechanism That Overcomes Cetuximab Induced Resistance
title_sort panitumumab egfr complex reveals a binding mechanism that overcomes cetuximab induced resistance
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033319/
https://www.ncbi.nlm.nih.gov/pubmed/27658254
http://dx.doi.org/10.1371/journal.pone.0163366
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