Abstract 1896: Whole transcriptome analysis identifies TNS4 as a key effector of cetuximab and a regulator of the oncogenic activity of KRAS mutant colorectal cancer cell lines

Abstract

Abstract Targeting of activated epidermal growth factor receptor (EGFR) with therapeutic anti-EGFR monoclonal antibodies (mAbs) such as cetuximab and panitumumab has been used as an effective strategy in treatment of colorectal cancer (CRC). However, its clinical efficacy occurs only in the limited number of patients. Here, we performed whole-transcriptome analysis in xenograft mouse tumors induced by KRASG12D mutation-bearing LS174T CRC cells following treatment with either cetuximab or PBS. By integrated analyses of differential gene expression with TCGA and CCLE public database, we identified TNS4, overexpressed in CRC patients and KRAS mutation-harboring CRC cell lines, significantly downregulated by cetuximab. While ablation of TNS4 expression via shRNA results in significant growth inhibition of LS174T, DLD1, WiDr, and DiFi CRC cell lines, conversely, its ectopic expression increases the oncogenic growth of these cells. Furthermore, TNS4 expression is transcriptionally regulated by MAP kinase signaling pathway. Consistent with this finding, selumetinib, a MEK1/2 inhibitor, suppressed oncogenic activity of CRC cells and this effect is more profound in combination with cetuximab. Altogether, we propose that TNS4 plays a crucial role in CRC tumorigenesis and that suppression of TNS4 would be an effective therapeutic strategy in treating a subset of cetuximab-refractory CRC patients including KRAS activating mutations. Citation Format: Sujin Kim, Nayoung Kim, Keunsoo Kang, Wonkyung Kim, Jonghwa Won, Jeonghee Cho. Whole transcriptome analysis identifies TNS4 as a key effector of cetuximab and a regulator of the oncogenic activity of KRAS mutant colorectal cancer cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1896.