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

Our work sheds new light on the influence of PRSS on cancer and the essential role of PRSS in mAb resistance, although recent studies have also demonstrated that tissue expression of trypsinogen correlates significantly with tumor aggressiveness, recurrence, and poor prognosis in CRC (34, 35) . Further analysis revealed that PRSS1 levels were closely associated with cetuximab resistance in mCRC. PRSS, which is produced and secreted by cancer cells, also mediates pro-urokinase and pro-matrix metalloproteinase activation, thus promoting/facilitating angiogenesis and tumor invasion by digesting components of the extracellular matrix (24) . The present findings raise the possibility that PRSS1 is a crucial determinant of resistance to cetuximab therapy in mCRC. First, we found significantly higher PRSS1 expression in cetuximab-resistant cells than that in cetuximabsensitive cells. Second, exogenous addition of PRSS1-enriched medium to human colon cancer cells (DiFi and LoVo cells) increased cetuximab resistance. Conversely, silencing PRSS1 in LoVo and HT-29 cells conferred cetuximab sensitivity. Third, both recombinant PRSS1 and the cell culture supernatants of the tested colon cancer cell lines cleaved cetuximab in the same manner. Furthermore, the most thorough cleavage was observed with the supernatant of HT-29 cells, which were the most resistant to cetuximab. Fourth, PRSS1 expression knockdown increased the cetuximab-mediated inhibition of pEGFR, pAKT, and pERK, while ectopic expression of PRSS1 decreased this inhibition. Therefore, we mechanistically demonstrated that PRSS1 cleaves mAbs, i.e., cetuximab, bevacizumab, and trastuzumab, thus decreasing the response to these antibodies and ultimately causing antibody resistance. Together, these findings suggest that PRSS may lead to antibody resistance by cleaving antibodies, eventually decreasing their efficacy.