Polymorphisms in genes involved in EGFR-turnover are predictive for cetuximab efficacy in colorectal cancer

Transmembrane receptors such as the epidermal growth factor receptor (EGFR) are regulated by their turnover, which is dependent on the ubiquitin-proteasome-system (UPS). We tested in two independent study cohorts whether single nucleotide polymorphisms (SNPs) in genes in-volved in EGFR turnover predict clinical outcome in cetuximab treated metastatic colorectal can-cer 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); UBE2L3 (rs5754216). SNPs showing an association with response or survival were analyzed in BRAF and RAS wild-type samples from the FIRE-3 study. 153 FOLFIRI plus cetuximab treated patients served as valida-tion set, 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 PFS (logrank-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 pre-dict efficacy of cetuximab in patients with mCRC. Genes involved in EGFR turnover may be new targets in the treatment of mCRC.