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

A rapidly accumulating body of evidence indicates that resistance to EGFR blockade in mCRC is parallel to or downstream of EGFR, mutations in RAS (exons 2 to 4) (12) , BRAF (exon 15) (13) , and PIK3CA (exon 20) (14, 15) , and amplification of the genes KRAS (16, 17) , HER2, and MET (18) . However, predicting responses to anti-EGFR mAbs in patients with mCRC remains challenging. Extensive research has determined that even in patients with tumors harboring wild-type KRAS, NRAS, BRAF, and PIK3CA, interindividual variability in the response to cetuximab exists, and that in a large proportion of responsive patients, acquired resistance to cetuximab emerges despite the absence of detectable mutations in RAS (17) , BRAF (19) , and PIK3CA (14) . In clinical practice, identifying specific and easily assayed secreted biomarkers for anti-EGFR mAbs is of paramount importance for predicting and monitoring the therapeutic response and resistance. Although RAS and BRAF have been identified as predictive and prognostic biomarkers for patients with mCRC treated with anti-EGFR mAbs, due to unmet clinical needs, we hypothesized that additional biomarkers may also contribute to anti-EGFR antibody efficacy. We demonstrate the possibility of using PRSS (a serine protease) as a predictive marker of the mCRC response to cetuximab treatment. PRSS1 encodes the pancreatic serine proteinase, which is also named trypsin-1, a major pancreatic digestive enzyme that also catalyzes the activation of other pancreatic zymogens into active enzymes, which normally occurs in the intestine (20) . A heterozygous PRSS1 pathogenic variant was identified to confirm the diagnosis of hereditary pancreatitis, inform treatment, and enable variant-specific testing of at-risk family members (20) . PRSS1 is expressed in a variety of cancer cell lines and tissues. Tumor-associated trypsinogens (21) are also strongly associated with the depth of invasion, lymph node metastasis, an advanced pathological tumornode-metastasis stage, and recurrence in ovarian cancer (22) , esophageal squamous cell carcinoma (23) , and CRC (24) .