Epidermal growth factor receptor mutation mediates cross-resistance to panitumumab and cetuximab in gastrointestinal cancer

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