Small Molecule T315 Promotes Casitas B-Lineage Lymphoma-Dependent Degradation of Epidermal Growth Factor Receptor via Y1045 Autophosphorylation
Despite the fact that tyrosine kinase inhibitors (TKIs) have been found effective in treating patients harboring activating mutations of epidermal growth factor receptor (EGFR), an acquired secondary mutation, T790M, which lowers the affinity to TKIs, can lead to EGFR TKI resistance after this stand...
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Veröffentlicht in: | American journal of respiratory and critical care medicine 2016-04, Vol.193 (7), p.753-766 |
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creator | Huang, Kuo-Yen Kao, Shih-Han Wang, Wen-Lung Chen, Chi-Yuan Hsiao, Tzu-Hung Salunke, Santosh B Chen, Jeremy J W Su, Kang-Yi Yang, Shuenn-Chen Hong, Tse-Ming Chen, Ching-Shih Yang, Pan-Chyr |
description | Despite the fact that tyrosine kinase inhibitors (TKIs) have been found effective in treating patients harboring activating mutations of epidermal growth factor receptor (EGFR), an acquired secondary mutation, T790M, which lowers the affinity to TKIs, can lead to EGFR TKI resistance after this standard treatment.
To evaluate the effect of small molecule T315 on EGFR degradation and its therapeutic efficacy in vitro and in vivo.
Lung adenocarcinoma cells were treated with T315, and cell proliferation and apoptotic proportion were determined by the CellTiter 96 AQueous MTS (3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium, inner salt) assay and flow cytometry. The effects of T315 on EGFR mRNA and protein levels, autophosphorylation, ubiquitination, and degradation were evaluated by real-time polymerase chain reaction and Western blot, respectively. Direct targeting of T315 to EGFR was confirmed by the in vitro kinase assay and mass spectrometry. Finally, the preclinical effect of T315 was validated in the murine xenograft model in combination with a second-generation TKI, afatinib.
We identified T315 as a novel, potent small molecule for suppressing cancer cell proliferation in vitro and in vivo. The therapeutic effect was verified after T315 was combined with a second-generation TKI, afatinib, compared with a single drug administration. We found a new mechanism of action, in that T315 appears to directly bind EGFR and triggers EGFR-Y1045 autophosphorylation, whereby its degradation is triggered through the ubiquitin-proteasome pathway.
Our evidence suggests that T315 is a novel class of anticancer drug that is able to inhibit the growth of EGFR-TKI-resistant lung adenocarcinoma cells by inducing the degradation of EGFR. |
doi_str_mv | 10.1164/rccm.201502-0250OC |
format | Article |
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To evaluate the effect of small molecule T315 on EGFR degradation and its therapeutic efficacy in vitro and in vivo.
Lung adenocarcinoma cells were treated with T315, and cell proliferation and apoptotic proportion were determined by the CellTiter 96 AQueous MTS (3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium, inner salt) assay and flow cytometry. The effects of T315 on EGFR mRNA and protein levels, autophosphorylation, ubiquitination, and degradation were evaluated by real-time polymerase chain reaction and Western blot, respectively. Direct targeting of T315 to EGFR was confirmed by the in vitro kinase assay and mass spectrometry. Finally, the preclinical effect of T315 was validated in the murine xenograft model in combination with a second-generation TKI, afatinib.
We identified T315 as a novel, potent small molecule for suppressing cancer cell proliferation in vitro and in vivo. The therapeutic effect was verified after T315 was combined with a second-generation TKI, afatinib, compared with a single drug administration. We found a new mechanism of action, in that T315 appears to directly bind EGFR and triggers EGFR-Y1045 autophosphorylation, whereby its degradation is triggered through the ubiquitin-proteasome pathway.
Our evidence suggests that T315 is a novel class of anticancer drug that is able to inhibit the growth of EGFR-TKI-resistant lung adenocarcinoma cells by inducing the degradation of EGFR.</description><identifier>ISSN: 1073-449X</identifier><identifier>EISSN: 1535-4970</identifier><identifier>DOI: 10.1164/rccm.201502-0250OC</identifier><identifier>PMID: 26583948</identifier><language>eng</language><publisher>United States: American Thoracic Society</publisher><subject>Adaptor Proteins, Signal Transducing - drug effects ; Adaptor Proteins, Signal Transducing - genetics ; Adenocarcinoma - drug therapy ; Adenocarcinoma - genetics ; Adenocarcinoma of Lung ; Afatinib ; Animals ; Antineoplastic Agents - adverse effects ; Antineoplastic Agents - therapeutic use ; Blotting, Western ; Cell Proliferation - drug effects ; Drug Combinations ; Drug Resistance, Neoplasm - drug effects ; Enzyme Assays ; ErbB Receptors - antagonists & inhibitors ; ErbB Receptors - drug effects ; ErbB Receptors - genetics ; Humans ; Lung Neoplasms - drug therapy ; Lung Neoplasms - genetics ; Mass Spectrometry ; Mice ; Mutation - genetics ; Protein Kinase Inhibitors - adverse effects ; Protein Kinase Inhibitors - therapeutic use ; Proto-Oncogene Proteins c-cbl - drug effects ; Proto-Oncogene Proteins c-cbl - genetics ; Quinazolines - adverse effects ; Quinazolines - therapeutic use ; Real-Time Polymerase Chain Reaction ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays</subject><ispartof>American journal of respiratory and critical care medicine, 2016-04, Vol.193 (7), p.753-766</ispartof><rights>Copyright American Thoracic Society Apr 1, 2016</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c380t-e7d6e6cd0bb3c182d9014d126a9fe0b2f8d9cb2d2b16d93df489c24672d6ef4c3</citedby><cites>FETCH-LOGICAL-c380t-e7d6e6cd0bb3c182d9014d126a9fe0b2f8d9cb2d2b16d93df489c24672d6ef4c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,4027,27931,27932</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26583948$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Kuo-Yen</creatorcontrib><creatorcontrib>Kao, Shih-Han</creatorcontrib><creatorcontrib>Wang, Wen-Lung</creatorcontrib><creatorcontrib>Chen, Chi-Yuan</creatorcontrib><creatorcontrib>Hsiao, Tzu-Hung</creatorcontrib><creatorcontrib>Salunke, Santosh B</creatorcontrib><creatorcontrib>Chen, Jeremy J W</creatorcontrib><creatorcontrib>Su, Kang-Yi</creatorcontrib><creatorcontrib>Yang, Shuenn-Chen</creatorcontrib><creatorcontrib>Hong, Tse-Ming</creatorcontrib><creatorcontrib>Chen, Ching-Shih</creatorcontrib><creatorcontrib>Yang, Pan-Chyr</creatorcontrib><title>Small Molecule T315 Promotes Casitas B-Lineage Lymphoma-Dependent Degradation of Epidermal Growth Factor Receptor via Y1045 Autophosphorylation</title><title>American journal of respiratory and critical care medicine</title><addtitle>Am J Respir Crit Care Med</addtitle><description>Despite the fact that tyrosine kinase inhibitors (TKIs) have been found effective in treating patients harboring activating mutations of epidermal growth factor receptor (EGFR), an acquired secondary mutation, T790M, which lowers the affinity to TKIs, can lead to EGFR TKI resistance after this standard treatment.
To evaluate the effect of small molecule T315 on EGFR degradation and its therapeutic efficacy in vitro and in vivo.
Lung adenocarcinoma cells were treated with T315, and cell proliferation and apoptotic proportion were determined by the CellTiter 96 AQueous MTS (3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium, inner salt) assay and flow cytometry. The effects of T315 on EGFR mRNA and protein levels, autophosphorylation, ubiquitination, and degradation were evaluated by real-time polymerase chain reaction and Western blot, respectively. Direct targeting of T315 to EGFR was confirmed by the in vitro kinase assay and mass spectrometry. Finally, the preclinical effect of T315 was validated in the murine xenograft model in combination with a second-generation TKI, afatinib.
We identified T315 as a novel, potent small molecule for suppressing cancer cell proliferation in vitro and in vivo. The therapeutic effect was verified after T315 was combined with a second-generation TKI, afatinib, compared with a single drug administration. We found a new mechanism of action, in that T315 appears to directly bind EGFR and triggers EGFR-Y1045 autophosphorylation, whereby its degradation is triggered through the ubiquitin-proteasome pathway.
Our evidence suggests that T315 is a novel class of anticancer drug that is able to inhibit the growth of EGFR-TKI-resistant lung adenocarcinoma cells by inducing the degradation of EGFR.</description><subject>Adaptor Proteins, Signal Transducing - drug effects</subject><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adenocarcinoma - drug therapy</subject><subject>Adenocarcinoma - genetics</subject><subject>Adenocarcinoma of Lung</subject><subject>Afatinib</subject><subject>Animals</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Blotting, Western</subject><subject>Cell Proliferation - drug effects</subject><subject>Drug Combinations</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Enzyme Assays</subject><subject>ErbB Receptors - antagonists & inhibitors</subject><subject>ErbB Receptors - drug effects</subject><subject>ErbB Receptors - genetics</subject><subject>Humans</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - genetics</subject><subject>Mass Spectrometry</subject><subject>Mice</subject><subject>Mutation - genetics</subject><subject>Protein Kinase Inhibitors - adverse effects</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Proto-Oncogene Proteins c-cbl - drug effects</subject><subject>Proto-Oncogene Proteins c-cbl - genetics</subject><subject>Quinazolines - adverse effects</subject><subject>Quinazolines - therapeutic use</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Tumor Cells, Cultured</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1073-449X</issn><issn>1535-4970</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNpdkc1O3DAURi1UBJT2BbpAlrphE_BfEnsJMwNFGkTVUqldRY59MxOUxMF2qOYpeGU8HWDRxZXv4nxHV_4Q-kLJGaWFOPfG9GeM0JywjLCc3M320BHNeZ4JVZIPaSclz4RQvw_RxxAeCKFMUnKADlmRS66EPELPP3vddfjWdWCmDvA9pzn-7l3vIgQ806GNOuDLbNkOoFeAl5t-XLteZ3MYYbAwRDyHlddWx9YN2DV4MbYWfLLia-_-xjW-0iY6j3-AgXG7PLUa_6FE5Phiii7ZQhq_6f4ZPqH9RncBPr--x-jX1eJ-9i1b3l3fzC6WmeGSxAxKW0BhLKlrbqhkVhEqLGWFVg2QmjXSKlMzy2paWMVtI6QyTBQlS7lGGH6MTnfe0bvHCUKs-jYY6Do9gJtCRcuyVFLIokzo1__QBzf5IV23pZQS6ctUotiOMt6F4KGpRt_22m8qSqptXdW2rmpXV7WrK4VOXtVT3YN9j7z1w18AMgmSmA</recordid><startdate>20160401</startdate><enddate>20160401</enddate><creator>Huang, Kuo-Yen</creator><creator>Kao, Shih-Han</creator><creator>Wang, Wen-Lung</creator><creator>Chen, Chi-Yuan</creator><creator>Hsiao, Tzu-Hung</creator><creator>Salunke, Santosh B</creator><creator>Chen, Jeremy J W</creator><creator>Su, Kang-Yi</creator><creator>Yang, Shuenn-Chen</creator><creator>Hong, Tse-Ming</creator><creator>Chen, Ching-Shih</creator><creator>Yang, Pan-Chyr</creator><general>American Thoracic Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope></search><sort><creationdate>20160401</creationdate><title>Small Molecule T315 Promotes Casitas B-Lineage Lymphoma-Dependent Degradation of Epidermal Growth Factor Receptor via Y1045 Autophosphorylation</title><author>Huang, Kuo-Yen ; Kao, Shih-Han ; Wang, Wen-Lung ; Chen, Chi-Yuan ; Hsiao, Tzu-Hung ; Salunke, Santosh B ; Chen, Jeremy J W ; Su, Kang-Yi ; Yang, Shuenn-Chen ; Hong, Tse-Ming ; Chen, Ching-Shih ; Yang, Pan-Chyr</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c380t-e7d6e6cd0bb3c182d9014d126a9fe0b2f8d9cb2d2b16d93df489c24672d6ef4c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adaptor Proteins, Signal Transducing - drug effects</topic><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Adenocarcinoma - drug therapy</topic><topic>Adenocarcinoma - genetics</topic><topic>Adenocarcinoma of Lung</topic><topic>Afatinib</topic><topic>Animals</topic><topic>Antineoplastic Agents - adverse effects</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Blotting, Western</topic><topic>Cell Proliferation - drug effects</topic><topic>Drug Combinations</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Enzyme Assays</topic><topic>ErbB Receptors - antagonists & inhibitors</topic><topic>ErbB Receptors - drug effects</topic><topic>ErbB Receptors - genetics</topic><topic>Humans</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - genetics</topic><topic>Mass Spectrometry</topic><topic>Mice</topic><topic>Mutation - genetics</topic><topic>Protein Kinase Inhibitors - adverse effects</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>Proto-Oncogene Proteins c-cbl - drug effects</topic><topic>Proto-Oncogene Proteins c-cbl - genetics</topic><topic>Quinazolines - adverse effects</topic><topic>Quinazolines - therapeutic use</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Tumor Cells, Cultured</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, Kuo-Yen</creatorcontrib><creatorcontrib>Kao, Shih-Han</creatorcontrib><creatorcontrib>Wang, Wen-Lung</creatorcontrib><creatorcontrib>Chen, Chi-Yuan</creatorcontrib><creatorcontrib>Hsiao, Tzu-Hung</creatorcontrib><creatorcontrib>Salunke, Santosh B</creatorcontrib><creatorcontrib>Chen, Jeremy J W</creatorcontrib><creatorcontrib>Su, Kang-Yi</creatorcontrib><creatorcontrib>Yang, Shuenn-Chen</creatorcontrib><creatorcontrib>Hong, Tse-Ming</creatorcontrib><creatorcontrib>Chen, Ching-Shih</creatorcontrib><creatorcontrib>Yang, Pan-Chyr</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>British Nursing Database</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><jtitle>American journal of respiratory and critical care medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huang, Kuo-Yen</au><au>Kao, Shih-Han</au><au>Wang, Wen-Lung</au><au>Chen, Chi-Yuan</au><au>Hsiao, Tzu-Hung</au><au>Salunke, Santosh B</au><au>Chen, Jeremy J W</au><au>Su, Kang-Yi</au><au>Yang, Shuenn-Chen</au><au>Hong, Tse-Ming</au><au>Chen, Ching-Shih</au><au>Yang, Pan-Chyr</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Small Molecule T315 Promotes Casitas B-Lineage Lymphoma-Dependent Degradation of Epidermal Growth Factor Receptor via Y1045 Autophosphorylation</atitle><jtitle>American journal of respiratory and critical care medicine</jtitle><addtitle>Am J Respir Crit Care Med</addtitle><date>2016-04-01</date><risdate>2016</risdate><volume>193</volume><issue>7</issue><spage>753</spage><epage>766</epage><pages>753-766</pages><issn>1073-449X</issn><eissn>1535-4970</eissn><abstract>Despite the fact that tyrosine kinase inhibitors (TKIs) have been found effective in treating patients harboring activating mutations of epidermal growth factor receptor (EGFR), an acquired secondary mutation, T790M, which lowers the affinity to TKIs, can lead to EGFR TKI resistance after this standard treatment.
To evaluate the effect of small molecule T315 on EGFR degradation and its therapeutic efficacy in vitro and in vivo.
Lung adenocarcinoma cells were treated with T315, and cell proliferation and apoptotic proportion were determined by the CellTiter 96 AQueous MTS (3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium, inner salt) assay and flow cytometry. The effects of T315 on EGFR mRNA and protein levels, autophosphorylation, ubiquitination, and degradation were evaluated by real-time polymerase chain reaction and Western blot, respectively. Direct targeting of T315 to EGFR was confirmed by the in vitro kinase assay and mass spectrometry. Finally, the preclinical effect of T315 was validated in the murine xenograft model in combination with a second-generation TKI, afatinib.
We identified T315 as a novel, potent small molecule for suppressing cancer cell proliferation in vitro and in vivo. The therapeutic effect was verified after T315 was combined with a second-generation TKI, afatinib, compared with a single drug administration. We found a new mechanism of action, in that T315 appears to directly bind EGFR and triggers EGFR-Y1045 autophosphorylation, whereby its degradation is triggered through the ubiquitin-proteasome pathway.
Our evidence suggests that T315 is a novel class of anticancer drug that is able to inhibit the growth of EGFR-TKI-resistant lung adenocarcinoma cells by inducing the degradation of EGFR.</abstract><cop>United States</cop><pub>American Thoracic Society</pub><pmid>26583948</pmid><doi>10.1164/rccm.201502-0250OC</doi><tpages>14</tpages></addata></record> |
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subjects | Adaptor Proteins, Signal Transducing - drug effects Adaptor Proteins, Signal Transducing - genetics Adenocarcinoma - drug therapy Adenocarcinoma - genetics Adenocarcinoma of Lung Afatinib Animals Antineoplastic Agents - adverse effects Antineoplastic Agents - therapeutic use Blotting, Western Cell Proliferation - drug effects Drug Combinations Drug Resistance, Neoplasm - drug effects Enzyme Assays ErbB Receptors - antagonists & inhibitors ErbB Receptors - drug effects ErbB Receptors - genetics Humans Lung Neoplasms - drug therapy Lung Neoplasms - genetics Mass Spectrometry Mice Mutation - genetics Protein Kinase Inhibitors - adverse effects Protein Kinase Inhibitors - therapeutic use Proto-Oncogene Proteins c-cbl - drug effects Proto-Oncogene Proteins c-cbl - genetics Quinazolines - adverse effects Quinazolines - therapeutic use Real-Time Polymerase Chain Reaction Tumor Cells, Cultured Xenograft Model Antitumor Assays |
title | Small Molecule T315 Promotes Casitas B-Lineage Lymphoma-Dependent Degradation of Epidermal Growth Factor Receptor via Y1045 Autophosphorylation |
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