cyy-287, a novel pyrimidine-2,4-diamine derivative, inhibits tumor growth of EGFR-driven non-small cell lung cancer via the ERK pathway
In recent decades, EGFR-targeted tyrosine kinase inhibitors (TKIs) have been proven to be an effective therapy for EGFR-mutant non-small cell lung cancer (NSCLC). However, resistance to EGFR-TKIs limits their clinical application. In the present study, we investigate the antitumor effect and underly...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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China Science Publishing & Media Ltd.
2022-10-01
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| Series: | Acta Biochimica et Biophysica Sinica |
| Subjects: | |
| Online Access: | https://www.sciengine.com/doi/10.3724/abbs.2022139 |
| _version_ | 1797635341991018496 |
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| author | Zhang Qianwen Huang Huijing Zheng Shuwen Tang Yelin Zhang Xiaodan Zhu Qianqian Ni Zefeng Zheng Xiaohui Wang Kun Huang Lehao Zhao Yunjie Liu Zhiguo Qian Jianchang |
| author_facet | Zhang Qianwen Huang Huijing Zheng Shuwen Tang Yelin Zhang Xiaodan Zhu Qianqian Ni Zefeng Zheng Xiaohui Wang Kun Huang Lehao Zhao Yunjie Liu Zhiguo Qian Jianchang |
| author_sort | Zhang Qianwen |
| collection | DOAJ |
| description | In recent decades, EGFR-targeted tyrosine kinase inhibitors (TKIs) have been proven to be an effective therapy for EGFR-mutant non-small cell lung cancer (NSCLC). However, resistance to EGFR-TKIs limits their clinical application. In the present study, we investigate the antitumor effect and underlying mechanism of a novel pyrimidine-2,4-diamine derivative, cyy-287, in NSCLC. We find that cyy-287 has a high affinity for lung tissue and inhibits the proliferation of NSCLC cells. Interestingly, the significant suppression of migration and induction of apoptosis by cyy-287 are only observed in EGFR-driven but not in EGFR-wild-type (wt) cells. According to the RNA sequencing and KEGG enrichment analysis results, cyy-287 markedly inhibits the MAPK pathway in EGFR-driven PC9 cells, and western blot analysis results further indicate that cyy-287 selectively blocks the ERK pathway in EGFR-driven cells. Meanwhile, apoptosis induced by cyy-287 could be partially reversed by ERK pathway inhibition. Further experiment indicates that cyy-287 inhibits the EGFR pathway in both EGFR-driven and EGFR-overexpressing cells. Interestingly, it only induces apoptosis in EGFR-driven cells, not in EGFR-overexpressing cells. The growth of EGFR-driven cells is suppressed by cyy-287 in vivo, with fewer side effects. Our results suggest that cyy-287 may be a potential therapeutic drug with promising antitumor effects against NSCLC. |
| first_indexed | 2024-03-11T12:20:50Z |
| format | Article |
| id | doaj.art-72546e3dd9804843b842af396e255b87 |
| institution | Directory Open Access Journal |
| issn | 1672-9145 |
| language | English |
| last_indexed | 2024-03-11T12:20:50Z |
| publishDate | 2022-10-01 |
| publisher | China Science Publishing & Media Ltd. |
| record_format | Article |
| series | Acta Biochimica et Biophysica Sinica |
| spelling | doaj.art-72546e3dd9804843b842af396e255b872023-11-07T01:02:05ZengChina Science Publishing & Media Ltd.Acta Biochimica et Biophysica Sinica1672-91452022-10-01541540155110.3724/abbs.202213920d259cccyy-287, a novel pyrimidine-2,4-diamine derivative, inhibits tumor growth of EGFR-driven non-small cell lung cancer via the ERK pathwayZhang Qianwen0Huang Huijing1Zheng Shuwen2Tang Yelin3Zhang Xiaodan4Zhu Qianqian5Ni Zefeng6Zheng Xiaohui7Wang Kun8Huang Lehao9Zhao Yunjie10Liu Zhiguo11Qian Jianchang12["Institute of Molecular Toxicology and Pharmacology, Wenzhou Medical University, Wenzhou 325035, China"]["Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China"]["Institute of Molecular Toxicology and Pharmacology, Wenzhou Medical University, Wenzhou 325035, China"]["Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China"]["Institute of Molecular Toxicology and Pharmacology, Wenzhou Medical University, Wenzhou 325035, China"]["Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China"]["Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China"]["Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China"]["Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China"]["Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China"]["Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China"]["Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China"]["Institute of Molecular Toxicology and Pharmacology, Wenzhou Medical University, Wenzhou 325035, China"]In recent decades, EGFR-targeted tyrosine kinase inhibitors (TKIs) have been proven to be an effective therapy for EGFR-mutant non-small cell lung cancer (NSCLC). However, resistance to EGFR-TKIs limits their clinical application. In the present study, we investigate the antitumor effect and underlying mechanism of a novel pyrimidine-2,4-diamine derivative, cyy-287, in NSCLC. We find that cyy-287 has a high affinity for lung tissue and inhibits the proliferation of NSCLC cells. Interestingly, the significant suppression of migration and induction of apoptosis by cyy-287 are only observed in EGFR-driven but not in EGFR-wild-type (wt) cells. According to the RNA sequencing and KEGG enrichment analysis results, cyy-287 markedly inhibits the MAPK pathway in EGFR-driven PC9 cells, and western blot analysis results further indicate that cyy-287 selectively blocks the ERK pathway in EGFR-driven cells. Meanwhile, apoptosis induced by cyy-287 could be partially reversed by ERK pathway inhibition. Further experiment indicates that cyy-287 inhibits the EGFR pathway in both EGFR-driven and EGFR-overexpressing cells. Interestingly, it only induces apoptosis in EGFR-driven cells, not in EGFR-overexpressing cells. The growth of EGFR-driven cells is suppressed by cyy-287 in vivo, with fewer side effects. Our results suggest that cyy-287 may be a potential therapeutic drug with promising antitumor effects against NSCLC. https://www.sciengine.com/doi/10.3724/abbs.2022139cyy-287non-small cell lung cancerEGFRERK |
| spellingShingle | Zhang Qianwen Huang Huijing Zheng Shuwen Tang Yelin Zhang Xiaodan Zhu Qianqian Ni Zefeng Zheng Xiaohui Wang Kun Huang Lehao Zhao Yunjie Liu Zhiguo Qian Jianchang cyy-287, a novel pyrimidine-2,4-diamine derivative, inhibits tumor growth of EGFR-driven non-small cell lung cancer via the ERK pathway Acta Biochimica et Biophysica Sinica cyy-287 non-small cell lung cancer EGFR ERK |
| title | cyy-287, a novel pyrimidine-2,4-diamine derivative, inhibits tumor growth of EGFR-driven non-small cell lung cancer via the ERK pathway |
| title_full | cyy-287, a novel pyrimidine-2,4-diamine derivative, inhibits tumor growth of EGFR-driven non-small cell lung cancer via the ERK pathway |
| title_fullStr | cyy-287, a novel pyrimidine-2,4-diamine derivative, inhibits tumor growth of EGFR-driven non-small cell lung cancer via the ERK pathway |
| title_full_unstemmed | cyy-287, a novel pyrimidine-2,4-diamine derivative, inhibits tumor growth of EGFR-driven non-small cell lung cancer via the ERK pathway |
| title_short | cyy-287, a novel pyrimidine-2,4-diamine derivative, inhibits tumor growth of EGFR-driven non-small cell lung cancer via the ERK pathway |
| title_sort | cyy 287 a novel pyrimidine 2 4 diamine derivative inhibits tumor growth of egfr driven non small cell lung cancer via the erk pathway |
| topic | cyy-287 non-small cell lung cancer EGFR ERK |
| url | https://www.sciengine.com/doi/10.3724/abbs.2022139 |
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