Author: 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
Title: PRSS contributes to cetuximab resistance in colorectal cancer Document date: 2020_1_1
ID: tymoeyoo_40
Snippet: The conventional PRSS1 cleavage site lies between the lysine and arginine residues; a PRSS1 cleavage site (between valine and threonine) in mAbs has never been reported. We also found that the PRSS1-mediated cleavage of mAbs was sequence specific and that modifying the amino acids L114 or T116 decreased the degree of mutant mAb cleavage by PRSS1 ( fig. S4, C and D) , which may be a theoretical basis for mAb modification. SPINK1 protects the pancr.....
Document: The conventional PRSS1 cleavage site lies between the lysine and arginine residues; a PRSS1 cleavage site (between valine and threonine) in mAbs has never been reported. We also found that the PRSS1-mediated cleavage of mAbs was sequence specific and that modifying the amino acids L114 or T116 decreased the degree of mutant mAb cleavage by PRSS1 ( fig. S4, C and D) , which may be a theoretical basis for mAb modification. SPINK1 protects the pancreas from autodigestion by preventing the activation of pancreatic proteases (26) . Unlike other inhibitors, namely, SBTI and ulinastatin, SPINK1 significantly suppressed the PRSS1-mediated cleavage of cetuximab and bevacizumab in vivo and in vitro. Our results showed that SPINK1 and cetuximab or bevacizumab had an additive effect on the inhibition of HT-29 and LoVo cell proliferation. This finding is consistent with the results of a report showing that combining mAbs with SPINK1 and EGFR led to a supra-additive reduction in the growth and invasion of SPINK1 + 22RV1 cells (31) . Furthermore, concomitant tumor expression of EGFR and TATI/SPINK1 is associated with a better prognosis in CRC (35) , indicating that anti-EGFR mAbs may produce a better response in SPINK1 + CRC cells, which further supports our findings.
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