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Predicting Agents That Can Overcome 5-FU Resistance in Colorectal Cancers via Pharmacogenomic Analysis

5-Fluorouracil (5-FU) is one of several chemotherapeutic agents in clinical use as a standard 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...

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Autores principales: Huang, Tsui-Chin, Peng, Kuan-Chieh, Kuo, Tzu-Ting, Lin, Li-Chun, Liu, Bai-Chia, Ye, Shu-Ping, Chu, Chien-Chou, Hsia, Shih-Min, Chang, Hsin-Yi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389646/
https://www.ncbi.nlm.nih.gov/pubmed/34440086
http://dx.doi.org/10.3390/biomedicines9080882
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author Huang, Tsui-Chin
Peng, Kuan-Chieh
Kuo, Tzu-Ting
Lin, Li-Chun
Liu, Bai-Chia
Ye, Shu-Ping
Chu, Chien-Chou
Hsia, Shih-Min
Chang, Hsin-Yi
author_facet Huang, Tsui-Chin
Peng, Kuan-Chieh
Kuo, Tzu-Ting
Lin, Li-Chun
Liu, Bai-Chia
Ye, Shu-Ping
Chu, Chien-Chou
Hsia, Shih-Min
Chang, Hsin-Yi
author_sort Huang, Tsui-Chin
collection PubMed
description 5-Fluorouracil (5-FU) is one of several chemotherapeutic agents in clinical use as a standard 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.
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spelling pubmed-83896462021-08-27 Predicting Agents That Can Overcome 5-FU Resistance in Colorectal Cancers via Pharmacogenomic Analysis Huang, Tsui-Chin Peng, Kuan-Chieh Kuo, Tzu-Ting Lin, Li-Chun Liu, Bai-Chia Ye, Shu-Ping Chu, Chien-Chou Hsia, Shih-Min Chang, Hsin-Yi Biomedicines Article 5-Fluorouracil (5-FU) is one of several chemotherapeutic agents in clinical use as a standard 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. MDPI 2021-07-24 /pmc/articles/PMC8389646/ /pubmed/34440086 http://dx.doi.org/10.3390/biomedicines9080882 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Huang, Tsui-Chin
Peng, Kuan-Chieh
Kuo, Tzu-Ting
Lin, Li-Chun
Liu, Bai-Chia
Ye, Shu-Ping
Chu, Chien-Chou
Hsia, Shih-Min
Chang, Hsin-Yi
Predicting Agents That Can Overcome 5-FU Resistance in Colorectal Cancers via Pharmacogenomic Analysis
title Predicting Agents That Can Overcome 5-FU Resistance in Colorectal Cancers via Pharmacogenomic Analysis
title_full Predicting Agents That Can Overcome 5-FU Resistance in Colorectal Cancers via Pharmacogenomic Analysis
title_fullStr Predicting Agents That Can Overcome 5-FU Resistance in Colorectal Cancers via Pharmacogenomic Analysis
title_full_unstemmed Predicting Agents That Can Overcome 5-FU Resistance in Colorectal Cancers via Pharmacogenomic Analysis
title_short Predicting Agents That Can Overcome 5-FU Resistance in Colorectal Cancers via Pharmacogenomic Analysis
title_sort predicting agents that can overcome 5-fu resistance in colorectal cancers via pharmacogenomic analysis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389646/
https://www.ncbi.nlm.nih.gov/pubmed/34440086
http://dx.doi.org/10.3390/biomedicines9080882
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