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

To confirm that high PRSS1 levels are clearly related to poor responses to mAbs (including cetuximab and bevacizumab) in different cancers, we analyzed the TCGA database of patients with other cancers who received antibody monotherapy. As PRSS1 expression is very low in head and neck squamous cell carcinoma (HNSCC) tissue, we divided the patients with HNSCC who received cetuximab monotherapy (n = 36) into high PRSS3 expression (n = 20) and low PRSS1 expression groups (n = 16) based on the median PRSS3 level of the HNSCC tissue samples in the TCGA database. As expected, the patients with low PRSS3 expression had significantly longer PFS than the patients with high expression (median survival, 323 days versus 150 days, respectively; P = 0.0397; Fig. 6E ). Furthermore, we determined whether PRSS expression affected the prognosis of patients with cancer. Consistent with previous studies, we found no significant difference in OS between the high-and low-PRSS3 groups ( fig. S8A ). We also divided the patients with colorectal adenocarcinoma who received bevacizumab monotherapy (n = 44) into high and low PRSS1 expression groups. The patients whose PRSS1 level exceeded the median PRSS1 level of all patients with colorectal carcinoma were assigned to the high-PRSS1 group (n = 24), and the remaining patients were assigned to the low-PRSS1 group (n = 20). Similar to the results for the patients with HNSCC, the patients with colorectal carcinoma with low PRSS1 expression had significantly longer PFS than the patients with high PRSS1 expression (median survival, 672 days versus 394 days, respectively; P = 0.0147; Fig. 6F and fig. S8B ). We also divided the patients with glioma who received bevacizumab monotherapy (n = 77) into two groups using the method used for the patients with HNSCC. Consistent with the results for the patients with HNSCC or colorectal carcinoma, the patients with glioma and low PRSS3 expression had longer PFS than the patients with high PRSS3 expression (median survival, 323 days versus 228 days, respectively; P = 0.0112; fig. S8, C and D) . The PRSS1 expression data were normalized in the patients with ovarian serous cystadenocarcinoma. Consequently, we divided the patients who received bevacizumab monotherapy (n = 53) into a high-PRSS1 expression group, where PRSS1 expression was less than zero (n = 39), and the low-PRSS1 expression group, where PRSS1 expression was zero and above (n = 14). Kaplan-Meier analysis of these patients consistently demonstrated much worse survival durations in the high-PRSS1 patients than those in the low-PRSS1 patients (median survival, 196 days versus 337 days, respectively; P = 0.0315; fig. S8 , E and F). Together, these findings suggested that high PRSS expression levels were associated with poor responses to mAb treatment.