Non‐canonical cMet regulation by vimentin mediates Plk1 inhibitor–induced apoptosis
Abstract To address the need for improved systemic therapy for non–small‐cell lung cancer (NSCLC), we previously demonstrated that mesenchymal NSCLC was sensitive to polo‐like kinase (Plk1) inhibitors, but the mechanisms of resistance in epithelial NSCLC remain unknown. Here, we show that cMet was d...
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| Format: | Article |
| Language: | English |
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Springer Nature
2019-04-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201809960 |
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| author | Ratnakar Singh Shaohua Peng Pavitra Viswanath Vaishnavi Sambandam Li Shen Xiayu Rao Bingliang Fang Jing Wang Faye M Johnson |
| author_facet | Ratnakar Singh Shaohua Peng Pavitra Viswanath Vaishnavi Sambandam Li Shen Xiayu Rao Bingliang Fang Jing Wang Faye M Johnson |
| author_sort | Ratnakar Singh |
| collection | DOAJ |
| description | Abstract To address the need for improved systemic therapy for non–small‐cell lung cancer (NSCLC), we previously demonstrated that mesenchymal NSCLC was sensitive to polo‐like kinase (Plk1) inhibitors, but the mechanisms of resistance in epithelial NSCLC remain unknown. Here, we show that cMet was differentially regulated in isogenic pairs of epithelial and mesenchymal cell lines. Plk1 inhibition inhibits cMet phosphorylation only in mesenchymal cells. Constitutively active cMet abrogates Plk1 inhibitor–induced apoptosis. Likewise, cMet silencing or inhibition enhances Plk1 inhibitor–induced apoptosis. Cells with acquired resistance to Plk1 inhibitors are more epithelial than their parental cells and maintain cMet activation after Plk1 inhibition. In four animal NSCLC models, mesenchymal tumors were more sensitive to Plk1 inhibition alone than were epithelial tumors. The combination of cMet and Plk1 inhibition led to regression of tumors that did not regrow when drug treatment was stopped. Plk1 inhibition did not affect HGF levels but did decrease vimentin phosphorylation, which regulates cMet phosphorylation via β1‐integrin. This research defines a heretofore unknown mechanism of ligand‐independent activation of cMet downstream of Plk1 and an effective combination therapy. |
| format | Article |
| id | doaj-art-4246619e4ece41939b17304846962bc4 |
| institution | OA Journals |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2019-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-4246619e4ece41939b17304846962bc42025-08-20T02:11:22ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-04-0111512010.15252/emmm.201809960Non‐canonical cMet regulation by vimentin mediates Plk1 inhibitor–induced apoptosisRatnakar Singh0Shaohua Peng1Pavitra Viswanath2Vaishnavi Sambandam3Li Shen4Xiayu Rao5Bingliang Fang6Jing Wang7Faye M Johnson8Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartment of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer Center Graduate School of Biomedical SciencesDepartment of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer CenterAbstract To address the need for improved systemic therapy for non–small‐cell lung cancer (NSCLC), we previously demonstrated that mesenchymal NSCLC was sensitive to polo‐like kinase (Plk1) inhibitors, but the mechanisms of resistance in epithelial NSCLC remain unknown. Here, we show that cMet was differentially regulated in isogenic pairs of epithelial and mesenchymal cell lines. Plk1 inhibition inhibits cMet phosphorylation only in mesenchymal cells. Constitutively active cMet abrogates Plk1 inhibitor–induced apoptosis. Likewise, cMet silencing or inhibition enhances Plk1 inhibitor–induced apoptosis. Cells with acquired resistance to Plk1 inhibitors are more epithelial than their parental cells and maintain cMet activation after Plk1 inhibition. In four animal NSCLC models, mesenchymal tumors were more sensitive to Plk1 inhibition alone than were epithelial tumors. The combination of cMet and Plk1 inhibition led to regression of tumors that did not regrow when drug treatment was stopped. Plk1 inhibition did not affect HGF levels but did decrease vimentin phosphorylation, which regulates cMet phosphorylation via β1‐integrin. This research defines a heretofore unknown mechanism of ligand‐independent activation of cMet downstream of Plk1 and an effective combination therapy.https://doi.org/10.15252/emmm.201809960cMetdrug combinationNSCLCPlk1vimentin |
| spellingShingle | Ratnakar Singh Shaohua Peng Pavitra Viswanath Vaishnavi Sambandam Li Shen Xiayu Rao Bingliang Fang Jing Wang Faye M Johnson Non‐canonical cMet regulation by vimentin mediates Plk1 inhibitor–induced apoptosis EMBO Molecular Medicine cMet drug combination NSCLC Plk1 vimentin |
| title | Non‐canonical cMet regulation by vimentin mediates Plk1 inhibitor–induced apoptosis |
| title_full | Non‐canonical cMet regulation by vimentin mediates Plk1 inhibitor–induced apoptosis |
| title_fullStr | Non‐canonical cMet regulation by vimentin mediates Plk1 inhibitor–induced apoptosis |
| title_full_unstemmed | Non‐canonical cMet regulation by vimentin mediates Plk1 inhibitor–induced apoptosis |
| title_short | Non‐canonical cMet regulation by vimentin mediates Plk1 inhibitor–induced apoptosis |
| title_sort | non canonical cmet regulation by vimentin mediates plk1 inhibitor induced apoptosis |
| topic | cMet drug combination NSCLC Plk1 vimentin |
| url | https://doi.org/10.15252/emmm.201809960 |
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