Genomic Characterization of Intrinsic and Acquired Resistance to Cetuximab in Colorectal Cancer Patients

Abstract

Background: Anti-EGFR antibodies are effective therapies for many late-stage colorectal cancer (CRC) patients; however, many tumors are unresponsive or develop resistance. Methods: We performed whole exome sequencing and RNA sequencing of 25 CRC patients who received cetuximab treatment. We obtained tissue specimens at acquired resistance and performed genomic analysis. Findings: Of 25 patients, 13 were categorized as intrinsic resistant and 12 were intrinsic sensitive tumor to cetuximab regardless of lines of therapy. Of 12 cetuximab sensitive tumors, we obtained 6 samples at acquired resistance to cetuximab. In the resistance group, we identified iNCOA4-RET and LMNA-NTRK1 fusions and NRG1 and GNAS amplifications without any aberrations in RAS/RAF pathway genes. For cetuximab-sensitive tumors, there were no major aberrations in the RAS pathway in all 12 tumors. Two PR patients showed KRAS K117N and A146T mutations, which are in KRAS exon 4 rather than in the more dominant exon 2. Other genomic aberrations found in the 12 PR patient cohort were BRAF V600E, AKT1 E17K, PIK3CA E542K, FGFR1, and ERBB2 CN amplifications. The comparison between baseline and at progression samples revealed an extreme loss and simultaneous gain of somatic variants in acquired resistance tumors suggesting that cetuximab exposure dramatically selected for rare resistant subclones of the baseline tumor that were initially undetectable. There was an increase in epithelial to mesenchymal transition (EMT) at acquired resistance with a reduction in the immune infiltrate. Interpretation: Each patient demonstrated varying genomic alterations which may facilitate in understanding the underlying culprit mechanism for cetuximab resistance at baseline. Funding Statement: This work was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C2750 to YSP, HI14C3418 to JL), the SMC Biobank (to HCK and JL). Declaration of Interests: Lilly employees: SB, PJE, JNC, IHW, TG, SSW, HQ, JCT, JL, MW, RDN, AA, CR No conflicts of interest declared (JL, STK, SYK, JYH, YSP, JOP, HL, WKK, HCK) Ethics Approval Statement: All study participants provided written informed consent and the study was approved by the institutional review board.