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

• Published in: Oncotarget Vol. 6; no. 14; pp. 12035 - 12047
• Main Authors: Braig, Friederike, März, Manuela, Schieferdecker, Aneta, Schulte, Alexander, Voigt, Mareike, Stein, Alexander, Grob, Tobias, Alawi, Malik, Indenbirken, Daniela, Kriegs, Malte, Engel, Erik, Vanhoefer, Udo, Grundhoff, Adam, Loges, Sonja, Riecken, Kristoffer, Fehse, Boris, Bokemeyer, Carsten, Binder, Mascha
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 20.05.2015
• Subjects: Adult; Aged; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - therapeutic use; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Cetuximab - administration & dosage; Cetuximab - therapeutic use; Female; Gastrointestinal Neoplasms - drug therapy; Humans; Male; Middle Aged; Mutation; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Research Paper; mutation; cetuximab; panitumumab; EGFR antibody resistance; circulating tumor DNA
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.3574

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.