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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| Format: | Article |
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MDPI AG
2021-07-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/9/8/882 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Tsui-Chin Huang |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T08:59:39Z |
| format | Article |
| id | doaj.art-a65c7be899784a0a98f873bffa727a54 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T08:59:39Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-a65c7be899784a0a98f873bffa727a542023-11-22T06:51:27ZengMDPI AGBiomedicines2227-90592021-07-019888210.3390/biomedicines9080882Predicting Agents That Can Overcome 5-FU Resistance in Colorectal Cancers via Pharmacogenomic AnalysisTsui-Chin Huang0Kuan-Chieh Peng1Tzu-Ting Kuo2Li-Chun Lin3Bai-Chia Liu4Shu-Ping Ye5Chien-Chou Chu6Shih-Min Hsia7Hsin-Yi Chang8Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, TaiwanGraduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, TaiwanPhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, TaiwanPhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, TaiwanGraduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, TaiwanGraduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, TaiwanGraduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, TaiwanGraduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, TaiwanGraduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan5-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.https://www.mdpi.com/2227-9059/9/8/8825-FU resistancecolorectal cancerdrug repurposingGenomics of Drug Sensitivity in CancerConnectivity Map |
| spellingShingle | 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 Predicting Agents That Can Overcome 5-FU Resistance in Colorectal Cancers via Pharmacogenomic Analysis Biomedicines 5-FU resistance colorectal cancer drug repurposing Genomics of Drug Sensitivity in Cancer Connectivity Map |
| 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 | 5-FU resistance colorectal cancer drug repurposing Genomics of Drug Sensitivity in Cancer Connectivity Map |
| url | https://www.mdpi.com/2227-9059/9/8/882 |
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