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 assess whether our experimental findings regarding PRSS1 are relevant to patients with mCRC in clinical practice, we used ELISA and immunoblotting analyses to examine whether PRSS1 levels can be used to determine mAb responses. We performed clinical validation using ELISA to measure serum PRSS1 levels in patients with mCRC receiving cetuximab treatment (data file S1). We collected serum samples from patients before treatment and every 4 to 8 weeks during treatment. The patients were categorized as partial response, stable disease, or progressive disease (PD) by radiological assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Among the 52 patients with mCRC who received cetuximab monotherapy, 25 patients with longitudinal serum samples eventually developed PD (data file S1). We compared changes in patient PRSS1 levels during antibody monotherapy and imaging results and found that PRSS1 levels gradually increased and reached a high level when PD occurred ( fig. S8G and data file S1). Specifically, compared with tumor markers such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), the circulating levels of PRSS1 in 16 of 25 patients were better correlated with the treatment outcome and reached a nadir when the best response to cetuximab was obtained. The levels of PRSS1 increased before tumor progression as determined by computerized tomography (CT). For nine patients, the PRSS1 levels during treatment did not appear to be associated with the treatment outcome; we postulate that these patients may have hyperactivation of the EGFR pathway downstream of the receptor or hyperactivation of other related pathways, which would uncouple PRSS1 secretion from the response to cetuximab treatment. Together, our findings indicated that serum PRSS1 levels correlated with treatment outcome according to standard radiological assessments.