Abstract 1412: High EGFR somatic mutation frequency targeting the TK domain in colorectal cancer patients with microsatellite instability (MSI)

Abstract

Abstract CRCs arise through genetic changes that impact various driver genes and in some tumors increased mutation rate in microsatellite unstable tumors. The hypermutable phenotype associated with microsatellite instability (MSI) results from loss of the mismatch repair system (MMR) activity. MSI is detected in 15% of all CRCs, and such tumors have a better prognosis and different chemotherapeutic outcome patterns, including high clinical benefit from immune checkpoint therapy or relative resistance to 5-FU as compared to microsatellite stable (MSS) tumors. The epidermal growth factor receptor (EGFR) signaling pathway plays an essential role in carcinogenesis of CRCs and is known to be overexpressed in MSI CRCs while highly mutated in Lung cancer. We analyzed the mutation frequency of deregulated pathways including EGFR and its downstream genes KRAS and BRAF in CRCs. We found a significantly elevated EGFR mutation frequency in CRC MSI-H subtype (45.5% vs. 6.5% in MSS CRCs, p<0.0000001). Although KRAS and NRAS are mutated with high frequency in both MSI-H and MSS groups, BRAF corresponding to RTK-RAS pathways is more altered in MSI-H than MSS CRCs (32.67% vs 13.10%; p=0.001), consistent with the known association between MSI-H CRCs and BRAF mutations. We hypothesized that there might be a mutation pattern in EGFR in CRC subtypes that provide a rationale for EGFR-targeted therapy for a subtype of CRC. Of 1104 profiled CRCs in the COSMIC v73 database, somatic EGFR mutations were mapped for 101 MSI-High versus 916 MSS CRCs. EGFR mutations mapped on the protein structure revealed that mutations are mainly targeting tyrosine kinase (TK) domain while the extracellular domain remained mostly wild-type with potential for targeting by anti-EGFR monoclonal antibodies. It is known that downstream genes such as KRAS as well as expression levels of EGFR ligands can affect the sensitivity of CRCs to anti-EGFR therapy. We didn’t detect any difference in mRNA expression level between MSI-H and MSS group but our analysis is indicative of the presence of G12D mutations in a high proportion of KRAS-mutated MSS CRCs, therefore resistance to anti-EGFR antibodies such as cetuximab would be expected. However, EGFR tyrosine kinase inhibitors such as erlotinib and gefitinib could be considered for further testing in patients with MSI-H tumors that have a lower frequency of G12D KRAS mutations and may have mutant EGFR. Citation Format: Safoora Deihimi, Michael Slifker, Eric A. Ross, Wafik S. El-Deiry. High EGFR somatic mutation frequency targeting the TK domain in colorectal cancer patients with microsatellite instability (MSI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1412. doi:10.1158/1538-7445.AM2017-1412