Format

Send to

Choose Destination
Oncotarget. 2015 May 20;6(14):12035-47.

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

Author information

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.

Abstract

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.

KEYWORDS:

EGFR antibody resistance; cetuximab; circulating tumor DNA; mutation; panitumumab

PMID:
26059438
PMCID:
PMC4494921
DOI:
10.18632/oncotarget.3574
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center