Combinational inhibition of EGFR and YAP reverses 5-Fu resistance in colorectal cancer

Changhao Huang¹, Zihua Chen¹, Chen Yang¹, Lu Chen¹, Chen Lai¹, Yingying Zhang², Weijie Yuan^1✉, Ji-Hak Jeong^3✉

1. Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
2. Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
3. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, 80 Daehak-ro, Buk-gu, 41566, Daegu, Republic of Korea

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Citation:
Huang C, Chen Z, Yang C, Chen L, Lai C, Zhang Y, Yuan W, Jeong JH. Combinational inhibition of EGFR and YAP reverses 5-Fu resistance in colorectal cancer. J Cancer 2020; 11(18):5432-5439. doi:10.7150/jca.44775. Available from https://www.jcancer.org/v11p5432.htm

Abstract

Yes-associated protein (YAP) is a transcriptional coactivator that promotes cell proliferation, migration, and tissue homeostasis in colorectal cancer (CRC). Here, we established 5-Fu resistant CRC cell line (SW620R) and examined the role of YAP in chemotherapy resistance. We showed that YAP promoted cell proliferation, migration, and chemotherapy resistance in CRC. To increase efficacy of CRC treatment, we employed another therapeutic target EGFR which interacts with the upstream signaling molecules of YAP in Hippo pathway. Verteporfin, a YAP specific inhibitor, inhibits YAP activity by blocking the YAP-TEAD complex in the cell nucleus, and AG1478, an inhibitor of EGFR/ErbB1, induces the phosphorylation and degradation of YAP. We found that combinational inhibition of YAP by VP and AG1478 synergistically suppressed the CRC development and reversed chemotherapy resistance in vitro and in vivo. Therefore, our results demonstrated a novel therapeutic strategy, the combination of inhibitors targeting EGFR and YAP, to suppress and reverse chemotherapy resistance in colorectal cancer.

Keywords: colorectal cancer, YAP, chemotherapy resistance, EGFR, 5-Fu