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.

doi:10.1371/journal.pone.0163366

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

Journal Article · Thu Sep 22 00:00:00 EDT 2016 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0163366· OSTI ID:1627803

^[1]; Kurzeja, Robert J. M. ^[2]; Michelsen, Klaus ^[1]; Vazir, Mukta ^[1]; Yang, Evelyn ^[1]; Tasker, Andrew S. ^[1]

Amgen Inc., Thousand Oaks, CA (United States). Dept. of Therapeutic Discovery
Amgen Inc., Thousand Oaks, CA (United States). Dept. of Metabolic Disorders

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.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1627803

Journal Information:: PLoS ONE, Vol. 11, Issue 9; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 44 works

Citation information provided by
Web of Science

References (28)

Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis De Roock, Wendy; Claes, Bart; Bernasconi, David The Lancet Oncology, Vol. 11, Issue 8 https://doi.org/10.1016/S1470-2045(10)70130-3	journal	August 2010
Structural basis for inhibition of the epidermal growth factor receptor by cetuximab Li, Shiqing; Schmitz, Karl R.; Jeffrey, Philip D. Cancer Cell, Vol. 7, Issue 4 https://doi.org/10.1016/j.ccr.2005.03.003	journal	April 2005
The S492R EGFR ectodomain mutation is never detected in KRAS wild-type colorectal carcinoma before exposure to EGFR monoclonal antibodies Esposito, Claudia; Rachiglio, Anna Maria; La Porta, Maria Libera Cancer Biology & Therapy, Vol. 14, Issue 12 https://doi.org/10.4161/cbt.26340	journal	December 2013
Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study Price, Timothy J.; Peeters, Marc; Kim, Tae Won The Lancet Oncology, Vol. 15, Issue 6 https://doi.org/10.1016/S1470-2045(14)70118-4	journal	May 2014
Epidermal growth factor receptor mutation mediates cross-resistance to panitumumab and cetuximab in gastrointestinal cancer Braig, Friederike; März, Manuela; Schieferdecker, Aneta Oncotarget, Vol. 6, Issue 14 https://doi.org/10.18632/oncotarget.3574	journal	March 2015
The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers Diaz Jr, Luis A.; Williams, Richard T.; Wu, Jian Nature, Vol. 486, Issue 7404 https://doi.org/10.1038/nature11219	journal	June 2012
Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer Montagut, Clara; Dalmases, Alba; Bellosillo, Beatriz Nature Medicine, Vol. 18, Issue 2 https://doi.org/10.1038/nm.2609	journal	January 2012
Frequency of S492R Mutations in the Epidermal Growth Factor Receptor: Analysis of Plasma Dna from Metastatic Colorectal Cancer Patients Treated with Panitumumab or Cetuximab Monotherapy Newhall, K.; Price, T.; Peeters, M. Annals of Oncology, Vol. 25 https://doi.org/10.1093/annonc/mdu193.11	journal	June 2014
Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer Misale, Sandra; Yaeger, Rona; Hobor, Sebastijan Nature, Vol. 486, Issue 7404 https://doi.org/10.1038/nature11156	journal	June 2012
Interactions of protein antigens with antibodies. Davies, D. R.; Cohen, G. H. Proceedings of the National Academy of Sciences, Vol. 93, Issue 1 https://doi.org/10.1073/pnas.93.1.7	journal	January 1996
Antibody-antigen interactions: new structures and new conformational changes Wilson, Ian A.; Stanfield, Robyn L. Current Opinion in Structural Biology, Vol. 4, Issue 6 https://doi.org/10.1016/0959-440X(94)90267-4	journal	January 1994
The epidermal growth factor receptor as a target for cancer therapy. Mendelsohn, J. Endocrine-related cancer https://doi.org/10.1677/erc.0.0080003	journal	March 2001
Epidermal growth factor receptor (EGFR) and KRAS mutations during chemotherapy plus anti-EGFR monoclonal antibody treatment in metastatic colorectal cancer Tougeron, David; Cortes, Ulrich; Ferru, Aurélie Cancer Chemotherapy and Pharmacology, Vol. 72, Issue 2 https://doi.org/10.1007/s00280-013-2211-0	journal	June 2013
Inference of Macromolecular Assemblies from Crystalline State Krissinel, Evgeny; Henrick, Kim Journal of Molecular Biology, Vol. 372, Issue 3 https://doi.org/10.1016/j.jmb.2007.05.022	journal	September 2007
Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy Yang, X. Critical Reviews in Oncology/Hematology, Vol. 38, Issue 1 https://doi.org/10.1016/S1040-8428(00)00134-7	journal	April 2001
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies Bettegowda, C.; Sausen, M.; Leary, R. J. Science Translational Medicine, Vol. 6, Issue 224 https://doi.org/10.1126/scitranslmed.3007094	journal	February 2014
Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer Van Cutsem, Eric; Köhne, Claus-Henning; Hitre, Erika New England Journal of Medicine, Vol. 360, Issue 14 https://doi.org/10.1056/NEJMoa0805019	journal	April 2009
Novel approaches to treatment of advanced colorectal cancer with anti‐EGFR monoclonal antibodies Zhang, Wu; Gordon, Michael; Lenz, Heinz‐Josef Annals of Medicine, Vol. 38, Issue 8 https://doi.org/10.1080/09546630601070812	journal	January 2006
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Functional Dissection of the Epidermal Growth Factor Receptor Epitopes Targeted by Panitumumab and Cetuximab Voigt, Mareike; Braig, Friederike; Göthel, Markus Neoplasia, Vol. 14, Issue 11 https://doi.org/10.1593/neo.121242	journal	November 2012
Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis De Roock, Wendy; Claes, Bart; Bernasconi, David The Lancet Oncology, Vol. 11, Issue 8, 753-762 https://doi.org/10.3410/f.5637957.5607056	journal	July 2010
ctDNA as promising tool for the assessment of minimal residual disease (MRD) and the need of an adjuvant treatment in gastroesophageal adenocarcinoma Piva, Vittoria Matilde; De Grandis, Maria Caterina; Zuin, Irene Sole Updates in Surgery, Vol. 75, Issue 2 https://doi.org/10.1007/s13304-022-01379-2	journal	October 2022
Crystal Structure of the Complex of Human Epidermal Growth Factor and Receptor Extracellular Domains Ogiso, Hideo; Ishitani, Ryuichiro; Nureki, Osamu Cell, Vol. 110, Issue 6 https://doi.org/10.1016/s0092-8674(02)00963-7	journal	September 2002
Targeting EGFR in colorectal cancer: beyond KRAS exon 2 Waddell, Tom The Lancet Oncology, Vol. 15, Issue 6 https://doi.org/10.1016/s1470-2045(14)70136-6	journal	May 2014
Tumor genotyping to predict response Myrvang, Helene Nature Reviews Clinical Oncology, Vol. 7, Issue 10 https://doi.org/10.1038/nrclinonc.2010.144	journal	September 2010
Emergence of Multiple EGFR Extracellular Mutations during Cetuximab Treatment in Colorectal Cancer Arena, S.; Bellosillo, B.; Siravegna, G. Clinical Cancer Research, Vol. 21, Issue 9 https://doi.org/10.1158/1078-0432.ccr-14-2821	journal	January 2015
When to screen and not to screen Cruickshanks, Nichola Cancer Biology & Therapy, Vol. 15, Issue 2 https://doi.org/10.4161/cbt.27741	journal	January 2014

Cited By (6)

RAS and BRAF mutations in cell‐free DNA are predictive for outcome of cetuximab monotherapy in patients with tissue‐tested RAS wild‐type advanced colorectal cancer Helden, Erik J.; Angus, Lindsay; Menke‐van der Houven van Oordt, C. Willemien Molecular Oncology, Vol. 13, Issue 11 https://doi.org/10.1002/1878-0261.12550	journal	September 2019
Targeting EGFR and RAS/RAF Signaling in the Treatment of Metastatic Colorectal Cancer: From Current Treatment Strategies to Future Perspectives Mizukami, Takuro; Izawa, Naoki; Nakajima, Takako Eguchi Drugs, Vol. 79, Issue 6 https://doi.org/10.1007/s40265-019-01113-0	journal	April 2019
Autophagy inhibitor facilitates gefitinib sensitivity in vitro and in vivo by activating mitochondrial apoptosis in triple negative breast cancer Liu, Zhaoyun; He, Kewen; Ma, Qinghua PLOS ONE, Vol. 12, Issue 5 https://doi.org/10.1371/journal.pone.0177694	journal	May 2017
Distinguishing Features of Cetuximab and Panitumumab in Colorectal Cancer and Other Solid Tumors García-Foncillas, Jesús; Sunakawa, Yu; Aderka, Dan Frontiers in Oncology, Vol. 9 https://doi.org/10.3389/fonc.2019.00849	journal	September 2019
Pharmacogenomics of Targeted Agents for Personalization of Colorectal Cancer Treatment Bignucolo, Alessia; De Mattia, Elena; Cecchin, Erika International Journal of Molecular Sciences, Vol. 18, Issue 7 https://doi.org/10.3390/ijms18071522	journal	July 2017
Monoclonal antibody-based molecular imaging strategies and theranostic opportunities Dammes, Niels; Peer, Dan Theranostics, Vol. 10, Issue 2 https://doi.org/10.7150/thno.37443	journal	January 2020

Figures / Tables (5)

Similar Records

KRAS Mutation Status and Clinical Outcome of Preoperative Chemoradiation With Cetuximab in Locally Advanced Rectal Cancer: A Pooled Analysis of 2 Phase II Trials

Journal Article · Tue Jan 01 00:00:00 EST 2013 · International Journal of Radiation Oncology, Biology and Physics · OSTI ID:1627803

Kim, Sun Young; Shim, Eun Kyung; Yeo, Hyun Yang; +7 more

Chemotherapy, Still an Option in the Twenty-First Century in Metastatic Colorectal Cancer?

Journal Article · Sun Sep 15 00:00:00 EDT 2019 · Cardiovascular and Interventional Radiology · OSTI ID:1627803

Eisterer, Wolfgang; Prager, Gerald

KRAS and BRAF Mutations and PTEN Expression Do Not Predict Efficacy of Cetuximab-Based Chemoradiotherapy in Locally Advanced Rectal Cancer

Journal Article · Tue Nov 15 00:00:00 EST 2011 · International Journal of Radiation Oncology, Biology and Physics · OSTI ID:1627803

Erben, Philipp; Stroebel, Philipp; Horisberger, Karoline; +9 more

Related Subjects

60 APPLIED LIFE SCIENCES
Science & Technology - Other Topics
Cancer therapies
colorectal cancer