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Mol Cancer Ther. 2015 Oct;14(10):2374-81. doi: 10.1158/1535-7163.MCT-15-0121. Epub 2015 Jul 23.

Polymorphisms in Genes Involved in EGFR Turnover Are Predictive for Cetuximab Efficacy in Colorectal Cancer.

Author information

1
USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Sharon Carpenter Laboatory, Los Angeles, California. Department for Medical Oncology and Comprehensive Cancer Center, University of Munich, Munich, Germany. sebastian.stintzing@med.uni-muenchen.de.
2
USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Sharon Carpenter Laboatory, Los Angeles, California.
3
Department for Medical Oncology and Comprehensive Cancer Center, University of Munich, Munich, Germany. German Cancer Consortium (DKTK); German Cancer Research Centre (DKFZ), Heidelberg, Germany.
4
Institute of Pathology, Paracelsus Medical University, Salzburger Landeskliniken (SALK), Salzburg, Austria.
5
Institute of Pathology, Paracelsus Medical University, Salzburger Landeskliniken (SALK), Salzburg, Austria. Medizinisches Versorgungszentrum für Histologie, Zytologie und Molekulare Diagnostik, Trier, Germany.
6
German Cancer Consortium (DKTK); German Cancer Research Centre (DKFZ), Heidelberg, Germany. Institute of Pathology, University of Munich, Munich, Germany.
7
Institute of Pathology, University of Munich, Munich, Germany.
8
Department of Preventive Dentistry and Periodontology, University of Munich, Munich, Germany.
9
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
10
USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Sharon Carpenter Laboatory, Los Angeles, California. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
11
USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Sharon Carpenter Laboatory, Los Angeles, California. Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
12
U.O. Oncologia Medica 2-Aziendo Ospedaliero-Universitaria Pisana, Pisa, Italy.
13
USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Sharon Carpenter Laboatory, Los Angeles, California. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.

Abstract

Transmembrane receptors, such as the EGFR, are regulated by their turnover, which is dependent on the ubiquitin-proteasome system. We tested in two independent study cohorts whether SNPs in genes involved in EGFR turnover predict clinical outcome in cetuximab-treated metastatic colorectal cancer (mCRC) patients. The following SNPs involved in EGFR degradation were analyzed in a screening cohort of 108 patients treated with cetuximab in the chemorefractory setting: c-CBL (rs7105971; rs4938637; rs4938638; rs251837), EPS15 (rs17567; rs7308; rs1065754), NAE1 (rs363169; rs363170; rs363172), SH3KBP1 (rs7051590; rs5955820; rs1017874; rs11795873), SGIP1 (rs604737; rs6570808; rs7526812), UBE2M (rs895364; rs895374), and UBE2L3 (rs5754216). SNPs showing an association with response or survival were analyzed in BRAF and RAS wild-type samples from the FIRE-3 study. One hundred and fifty-three FOLFIRI plus cetuximab-treated patients served as validation set, and 168 patients of the FOLFIRI plus bevacizumab arm served as controls. EGFR FISH was done in 138 samples to test whether significant SNPs were associated with EGFR expression. UBE2M rs895374 was significantly associated with progression-free survival (log-rank P = 0.005; HR, 0.60) within cetuximab-treated patients. No association with bevacizumab-treated patients (n = 168) could be established (P = 0.56; HR, 0.90). rs895374 genotype did not affect EGFR FISH measurements. EGFR recycling is an interesting mechanism of secondary resistance to cetuximab in mCRC. This is the first report suggesting that germline polymorphisms in the degradation process predict efficacy of cetuximab in patients with mCRC. Genes involved in EGFR turnover may be new targets in the treatment of mCRC.

PMID:
26206335
PMCID:
PMC4596768
DOI:
10.1158/1535-7163.MCT-15-0121
[Indexed for MEDLINE]
Free PMC Article

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