PRSS contributes to cetuximab resistance in colorectal cancer

Cetuximab improves the survival of patients with metastatic colorectal cancer. The main limitation is primary and secondary resistance, the underlying mechanism of which requires extensive investigation. We proved that PRSS expression levels are significantly negatively associated with the sensitivi...

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Published in:Science advances 2020-01, Vol.6 (1), p.eaax5576-eaax5576
Main Authors: 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
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container_title Science advances
container_volume 6
creator 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
description Cetuximab improves the survival of patients with metastatic colorectal cancer. The main limitation is primary and secondary resistance, the underlying mechanism of which requires extensive investigation. We proved that PRSS expression levels are significantly negatively associated with the sensitivity of cancer cells to cetuximab. Detailed mechanistic analysis indicated that PRSS can cleave cetuximab, leading to resistance. Cetuximab or bevacizumab combined with SPINK1, a PRSS inhibitor, inhibited cell growth more efficiently than cetuximab or bevacizumab alone in xenograft models. PRSS levels in the serum of 156 patients with mCRC were analyzed, and poor efficacy of cetuximab therapy was observed in patients with aberrant PRSS expression. PRSS expression in monoclonal antibody (mAb)-treated patients with cancer from The Cancer Genome Atlas database was also evaluated to determine whether patients with higher PRSS expression have significantly reduced progression-free survival. Our work provides a strong scientific rationale for targeting PRSS in combination with cetuximab therapy.
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SciAdv r-articles
title PRSS contributes to cetuximab resistance in colorectal cancer
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