PRSS contributes to cetuximab resistance in colorectal cancer

Tan, Zhaoli; Gao, Lihua; Wang, Yan; Yin, Huihui; Xi, Yongyi; Wu, Xiaojie; Shao, Yong; Qiu, Weiyi; Du, Peng; Shen, Wenlong; Fu, Ling; Jia, Ru; Zhao, Chuanhua; Zhang, Yun; Zhao, Zhihu; Sun, Zhiwei; Chen, Hongxing; Hu, Xianwen; Xu, Jianming; Wang, Youliang

EGFR and can be activated by EGFR ligands binding to the extracellular domain of EGFR to drive cell proliferation, survival, and invasion (26, 27) . Cetuximab acts by blocking ligand binding to the EGFR extracellular domain, thereby preventing ligand-mediated EGFR signaling and inhibiting increases in phosphorylated ERK (pERK) and phosphorylated AKT (pAKT) levels (Fig. 2, A to D) . Hence, to further elucidate the role of PRSS1 in cetuximab resistance, we performed immunoblotting for phosphorylated EGFR (pEGFR), pERK, and pAKT in stable PRSS1 expression knockdown LoVo cells and HT-29 cells. pEGFR, pERK, and pAKT levels were increased in shPRSS1-1 and shPRSS1-2 cells compared with those in shSCRM (scrambled) cells (Fig. 2, A and B ). Next, we examined whether exogenous addition of PRSS1-enriched medium to colon cancer cells would decrease the cetuximab-mediated inhibition of PI3K/AKT and MEK/ ERK signaling. As anticipated, ectopic PRSS1 expression in DiFi and LoVo cells decreased the cetuximab-mediated inhibition of pEGFR, pERK, and pAKT (Fig. 2 , C and D). In conclusion, PRSS1 expression knockdown increases the cetuximab-mediated inhibition of PI3K/AKT and MEK/ERK; conversely, ectopic PRSS1 expression decreases this inhibition. That is, the mechanism by which PRSS1 causes cetuximab resistance involves PRSS1 decreasing the efficacy of cetuximab.