Predicting agents that can overcome 5-FU resistance in colorectal cancers via pharmacogenomic analysis

Tsui Chin Huang, Kuan Chieh Peng, Tzu Ting Kuo, Li Chun Lin, Bai Chia Liu, Shu Ping Ye, Chien Chou Chu, Shih Min Hsia, Hsin Yi Chang

研究成果: 雜誌貢獻文章同行評審

摘要

5-Fluorouracil (5-FU) is one of several chemotherapeutic agents in clinical use as a stan-dard of care to treat colorectal cancers (CRCs). As an antimetabolite, 5-FU inhibits thymidylate synthase to disrupt the synthesis and repair of DNA and RNA. However, only a small proportion of patients benefit from 5-FU treatment due to the development of drug resistance. This study applied pharmacogenomic analysis using two public resources, the Genomics of Drug Sensitivity in Cancer (GDSC) and the Connectivity Map, to predict agents overcoming 5-FU resistance in CRC cells based on their genetic background or gene expression profile. Based on the genetic status of adenomatous polyposis coli (APC), the most frequent mutated gene found in CRC, we found that combining a MEK inhibitor with 5-FU exhibited synergism effects on CRC cells with APC truncations. While considering the gene expression in 5-FU resistant cells, we demonstrated that targeting ROCK is a potential avenue to restore 5-FU response to resistant cells with wild-type APC background. Our results reveal MEK signaling plays a pivotal role in loss-of-function, APC-mediated 5-FU resistance, and ROCK activation serves as a signature in APC-independent 5-FU resistance. Through the use of these available database resources, we highlight possible approaches to predict potential drugs for combinatorial therapy for patients developing resistance to 5-FU treatment.
原文英語
文章編號882
期刊Biomedicines
9
發行號8
DOIs
出版狀態已發佈 - 8月 2021

ASJC Scopus subject areas

  • 醫藥(雜項)
  • 生物化學、遺傳與分子生物學 (全部)

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