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

Abstract

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 involved in EGFR turnover predict clinical outcome in cetuximab treated metastatic colorectal cancer 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 validation 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 predict efficacy of cetuximab in patients with mCRC. Genes involved in EGFR turnover may be new targets in the treatment of mCRC.

An Ex Vivo Human Tumor Assay Shows Distinct Patterns of EGFR Trafficking in Squamous Cell Carcinoma Correlating to Therapeutic Outcomes

“…EGFR activation is responsible for the cellular secretion of proteins involved in antimicrobial defense (Pastore et al, 2008). A number of single-nucleotide polymorphisms identified as predictive for anti-EGFR therapy are involved in the trafficking and internalization of EGFR, including polymorphisms in c-CBL and EPS15 (Stintzing et al, 2015), suggesting that polarization or dysregulation of EGFR trafficking may in part determine patient therapeutic response.…”

Mechanisms of Innate and Acquired Resistance to Anti-EGFR Therapy: A Review of Current Knowledge with a Focus on Rechallenge Therapies

“…(82) EGFR recycling could be an interesting mechanism of secondary resistance to cetuximab in mCRC and is also a putative mechanism for PTEN induced EGFRi resistance. (28,82) Further studies are needed to validate these preliminary data.…”

“…Single nucleotide polymorphisms (SNPs) in candidate genes associated with regulating the EGFR pathway communication also appeared to be of predictive value in several reports. (82) In particular, Stintzing et al have identified SNPs in genes involved in EGFR turnover that predicted clinical outcome in cetuximab-treated mCRC patients. (82) EGFR recycling could be an interesting mechanism of secondary resistance to cetuximab in mCRC and is also a putative mechanism for PTEN induced EGFRi resistance.…”

The cross talk of ubiquitination and chemotherapy tolerance in colorectal cancer

“…The therapeutic efficacy of cetuximab is often compromised by acquired drug resistance; however, the mechanisms underlying this phenomenon are still unknown. Computer simulations have shown that multiple ubiquitination-related protein gene polymorphisms are involved in EGFR turnover and predict the efficacy of cetuximab, such as the ubiquitin-binding enzyme UBE2M and ubiquitin-conjugating enzyme E2L3 (UBE2L3), which may affect secondary resistance to cetuximab in metastatic CRC (Stintzing et al 2015 ). Moreover, previous reports have shown that resistance to cetuximab in CRC is associated with increased expression of c-Myc, which significantly reduces apoptosis (Boos et al 2022 ).…”