Epidermal growth factor receptor mutation mediates cross-resistance to panitumumab and cetuximab in gastrointestinal cancer
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Friederike Braig1, Manuela März1, Aneta Schieferdecker1, Alexander Schulte2, Mareike Voigt1, Alexander Stein1, Tobias Grob3, Malik Alawi4, Daniela Indenbirken5, Malte Kriegs6, Erik Engel7, Udo Vanhoefer8, Adam Grundhoff5, Sonja Loges1,9, Kristoffer Riecken10, Boris Fehse10, Carsten Bokemeyer1 and Mascha Binder1
1 Department of Oncology and Hematology, BMT with section Pneumology, Hubertus Wald Tumorzentrum / UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
2 Department of Neurosurgery, Laboratory for Brain Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
3 Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
4 Bioinformatics Service Facility, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
5 Heinrich-Pette-Institute, Leibniz-Institute for Experimental Virology (HPI), Hamburg, Germany
6 Radiation Biology and Radio-Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
7 Hämatologisch-onkologische Praxis Altona (HOPA), Hamburg, Germany
8 Marienkrankenhaus, Zentrum für Innere Medizin, Hamburg, Germany
9 Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
10 Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Mascha Binder, email:
Keywords: panitumumab, cetuximab, EGFR antibody resistance, mutation, circulating tumor DNA
Received: January 30, 2015 Accepted: February 20, 2015 Published: March 14, 2015
Acquired resistance to epidermal growth factor receptor (EGFR) targeted antibodies represents a clinical challenge in the treatment of gastrointestinal tumors such as metastatic colorectal cancer, but its molecular mechanisms are incompletely understood. We scanned KRAS exon 2/3/4, NRAS exon 2/3/4 and the overlapping epitopes of the EGFR antibodies cetuximab and panitumumab for mutations in pre- and post-treatment tumor tissue of 21 patients with gastrointestinal cancer treated with chemotherapy +/- EGFR antibodies by next-generation sequencing (“tumor tissue” cohort). We describe a novel EGFR exon 12 mutation acquired in tumors of 1 out of 3 patients treated with panitumumab. The EGFR G465R mutation introduces a positive charge within the overlap of the panitumumab and cetuximab epitopes. It abrogates antibody binding and mediates cross-resistance to both antibodies in EGFR G465R-transfected Ba/F3 cells. In circulating tumor DNA from an independent “liquid biopsy” cohort of 27 patients, we found this novel mutation in 1 out of 6 panitumumab-treated cases while about one third of patients show acquired RAS mutations. We show that acquired resistance by epitope-changing mutations also emerges during panitumumab treatment, which can be easily detected by a liquid biopsy approach even before clinical resistance occurs and this may help in tailoring EGFR-targeted therapies.
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