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 data also revealed that administering an anti-EGFR mAb (cetuximab) or bevacizumab to mice bearing HT-29 xenografts attenuated tumor growth by more than 19 and 23%, respectively, and by approximately 40 and 49%, respectively, when combined with SPINK1. Moreover, administering cetuximab to mice bearing LoVo xenografts attenuated tumor growth by more than 29% and by approximately 46% when combined with SPINK1 (Fig. 5, A, B, and D) . Administering SPINK1 alone to mice bearing HT-29 or LoVo xenografts promoted tumor growth (Fig. 5, A, B, and D) , which is consistent with previous studies reporting that extracellular SPINK1 promotes cell proliferation by down-regulating metallothionein expression (26) and interacting with EGFR to activate downstream signaling as SPINK1 is structurally similar to EGF (31). Together, our findings indicate that the functional significance of PRSS1 in cetuximab resistance warrants further investigation to identify a more effective inhibitor of PRSS1 as a therapy for patients with mCRC. Specifically, PRSS1 blockade may be a viable option for patients with mCRC with a high-serum PRSS1 level who are resistant to anti-EGFR therapies.