Bruton’s tyrosine kinase (BTK) mediates resistance to EGFR inhibition in non-small-cell lung carcinoma
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are current standard of care for patients with EGFR mutation and metastatic non-small-cell lung carcinoma (NSCLC), but most patients using EGFR TKIs acquire resistance later. So, overcoming resistance of EGFR TKIs has become a...
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creator | Yeh, Chi-Tai Chen, Tzu-Tao Satriyo, Pamungkas Bagus Wang, Chun-Hua Wu, Alexander T. H. Chao, Tsu-Yi Lee, Kang-Yun Hsiao, Michael Wang, Liang-Shun Kuo, Kuang-Tai |
description | Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are current standard of care for patients with EGFR mutation and metastatic non-small-cell lung carcinoma (NSCLC), but most patients using EGFR TKIs acquire resistance later. So, overcoming resistance of EGFR TKIs has become an important issue in the treatment of NSCLC. Previously, therapeutics targeting Bruton’s tyrosine kinase (BTK) have been successful in treating several hematologic malignancies. However, the role of BTK in NSCLC is still unknown. In this study, by examining surgical specimens from 80 NSCLC patients and their clinicopathologic parameters, we found significant correlation between high BTK expression and tumor differentiation, p-stage, lymph node metastatic status, maximum tumor size, and poor prognosis of patients. Using two NSCLC cell lines A540 and PC9, we demonstrated that BTK
pos
cells exhibited more stemness (OCT4, SOX2) and EMT (E-Cadherin, Slug) markers than BTK
neg
cells. Knockdown of BTK sensitized the NSCLC cells to Gefitinib. Meanwhile, the second-generation BTK inhibitor Acalabrutinib effectively suppressed SOX2, STAT3/JAK2/Akt axis and potentiated the anti-proliferative effect of Gefitinib and Osimertinib in NSCLC cells, including the T790M H1975 cells. Furthermore, Acalabrutinib and Osimertinib combination exhibited significant tumor growth inhibition of H1975-derived tumors in vivo. Our findings suggested that BTK mediates stemness and EMT properties, and inhibition of BTK potentiates the effect of Gefitinib and Osimertinib in NSCLC cells resistant to TKI. This implies a new approach to treat the NSCLC patients with resistance to previous TKI treatment. |
doi_str_mv | 10.1038/s41389-021-00345-8 |
format | Article |
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pos
cells exhibited more stemness (OCT4, SOX2) and EMT (E-Cadherin, Slug) markers than BTK
neg
cells. Knockdown of BTK sensitized the NSCLC cells to Gefitinib. Meanwhile, the second-generation BTK inhibitor Acalabrutinib effectively suppressed SOX2, STAT3/JAK2/Akt axis and potentiated the anti-proliferative effect of Gefitinib and Osimertinib in NSCLC cells, including the T790M H1975 cells. Furthermore, Acalabrutinib and Osimertinib combination exhibited significant tumor growth inhibition of H1975-derived tumors in vivo. Our findings suggested that BTK mediates stemness and EMT properties, and inhibition of BTK potentiates the effect of Gefitinib and Osimertinib in NSCLC cells resistant to TKI. This implies a new approach to treat the NSCLC patients with resistance to previous TKI treatment.</description><identifier>ISSN: 2157-9024</identifier><identifier>EISSN: 2157-9024</identifier><identifier>DOI: 10.1038/s41389-021-00345-8</identifier><identifier>PMID: 34315851</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/100 ; 13/109 ; 13/2 ; 13/31 ; 13/51 ; 13/89 ; 631/154/53/2422 ; 631/67/1612/1350 ; AKT protein ; Apoptosis ; Bruton's tyrosine kinase ; Cell Biology ; E-cadherin ; Epidermal growth factor ; Epidermal growth factor receptors ; Gefitinib ; Human Genetics ; Internal Medicine ; Janus kinase 2 ; Life Sciences & Biomedicine ; Lung cancer ; Lung carcinoma ; Lymph nodes ; Medicine ; Medicine & Public Health ; Metastases ; Metastasis ; Non-small cell lung carcinoma ; Oct-4 protein ; Oncology ; Patients ; Protein-tyrosine kinase ; Science & Technology ; Stat3 protein ; Targeted cancer therapy ; Tumors</subject><ispartof>Oncogenesis (New York, NY), 2021-07, Vol.10 (7), p.56-56, Article 56</ispartof><rights>The Author(s) 2021</rights><rights>The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>7</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000678060500001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c447t-4b82659e3e6f45aa379133a049cf9022659b76078c15af29fc1142af163ef3a3</citedby><cites>FETCH-LOGICAL-c447t-4b82659e3e6f45aa379133a049cf9022659b76078c15af29fc1142af163ef3a3</cites><orcidid>0000-0003-2754-2283 ; 0000-0002-0178-6530 ; 0000-0001-8529-9213 ; 0000-0001-9544-3119</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316404/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316404/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2115,27929,27930,39263,41125,42194,51581,53796,53798</link.rule.ids></links><search><creatorcontrib>Yeh, Chi-Tai</creatorcontrib><creatorcontrib>Chen, Tzu-Tao</creatorcontrib><creatorcontrib>Satriyo, Pamungkas Bagus</creatorcontrib><creatorcontrib>Wang, Chun-Hua</creatorcontrib><creatorcontrib>Wu, Alexander T. H.</creatorcontrib><creatorcontrib>Chao, Tsu-Yi</creatorcontrib><creatorcontrib>Lee, Kang-Yun</creatorcontrib><creatorcontrib>Hsiao, Michael</creatorcontrib><creatorcontrib>Wang, Liang-Shun</creatorcontrib><creatorcontrib>Kuo, Kuang-Tai</creatorcontrib><title>Bruton’s tyrosine kinase (BTK) mediates resistance to EGFR inhibition in non-small-cell lung carcinoma</title><title>Oncogenesis (New York, NY)</title><addtitle>Oncogenesis</addtitle><addtitle>ONCOGENESIS</addtitle><description>Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are current standard of care for patients with EGFR mutation and metastatic non-small-cell lung carcinoma (NSCLC), but most patients using EGFR TKIs acquire resistance later. So, overcoming resistance of EGFR TKIs has become an important issue in the treatment of NSCLC. Previously, therapeutics targeting Bruton’s tyrosine kinase (BTK) have been successful in treating several hematologic malignancies. However, the role of BTK in NSCLC is still unknown. In this study, by examining surgical specimens from 80 NSCLC patients and their clinicopathologic parameters, we found significant correlation between high BTK expression and tumor differentiation, p-stage, lymph node metastatic status, maximum tumor size, and poor prognosis of patients. Using two NSCLC cell lines A540 and PC9, we demonstrated that BTK
pos
cells exhibited more stemness (OCT4, SOX2) and EMT (E-Cadherin, Slug) markers than BTK
neg
cells. Knockdown of BTK sensitized the NSCLC cells to Gefitinib. Meanwhile, the second-generation BTK inhibitor Acalabrutinib effectively suppressed SOX2, STAT3/JAK2/Akt axis and potentiated the anti-proliferative effect of Gefitinib and Osimertinib in NSCLC cells, including the T790M H1975 cells. Furthermore, Acalabrutinib and Osimertinib combination exhibited significant tumor growth inhibition of H1975-derived tumors in vivo. Our findings suggested that BTK mediates stemness and EMT properties, and inhibition of BTK potentiates the effect of Gefitinib and Osimertinib in NSCLC cells resistant to TKI. This implies a new approach to treat the NSCLC patients with resistance to previous TKI treatment.</description><subject>13</subject><subject>13/100</subject><subject>13/109</subject><subject>13/2</subject><subject>13/31</subject><subject>13/51</subject><subject>13/89</subject><subject>631/154/53/2422</subject><subject>631/67/1612/1350</subject><subject>AKT protein</subject><subject>Apoptosis</subject><subject>Bruton's tyrosine kinase</subject><subject>Cell Biology</subject><subject>E-cadherin</subject><subject>Epidermal growth factor</subject><subject>Epidermal growth factor receptors</subject><subject>Gefitinib</subject><subject>Human Genetics</subject><subject>Internal Medicine</subject><subject>Janus kinase 2</subject><subject>Life Sciences & Biomedicine</subject><subject>Lung cancer</subject><subject>Lung carcinoma</subject><subject>Lymph nodes</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Non-small cell lung carcinoma</subject><subject>Oct-4 protein</subject><subject>Oncology</subject><subject>Patients</subject><subject>Protein-tyrosine kinase</subject><subject>Science & Technology</subject><subject>Stat3 protein</subject><subject>Targeted cancer therapy</subject><subject>Tumors</subject><issn>2157-9024</issn><issn>2157-9024</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>HGBXW</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNUk1v1DAQtRCIVkv_ACdLXIpQwI4_4lyQ6KotFZWQ0N4txzvZ9ZK1i-2AeuNv8Pf4JTibqlAOCF888rx5nnnzEHpOyWtKmHqTOGWqrUhNK0IYF5V6hI5rKpqqJTV__Ed8hE5S2pFyhKRSiKfoiHFGhRL0GG3P4piD__n9R8L5NobkPODPzpsE-PRs9eEl3sPamQwJR0guZeMt4Bzw-eXFJ-z81nUuu-BLiH3wVdqbYagsDAMeRr_B1kTrfNibZ-hJb4YEJ3f3Aq0uzlfL99X1x8ur5bvrynLe5Ip3qpaiBQay58IY1rSUMUN4a_syzJTrGkkaZakwfd32llJem55KBj0zbIGuZtp1MDt9E93exFsdjNOHhxA32sTs7ACaSAutbRXjSnJLrKrXXVc-4BT4uikSLdDbmetm7IoKFnyOZnhA-jDj3VZvwletGJWcTASndwQxfBkhZb13adLGeAhj0rUQoi0bOUBf_AXdhTH6otQBxRVnDSuoekbZsqkUob9vhhI92ULPttDFFvpgi9LLAqm56Bt0oU_WQVnhfWGxhWwUkURMDqFLl820z2UYfS6lr_6_tKDZjE4F4TcQf8_wj_Z-AQ322VM</recordid><startdate>20210727</startdate><enddate>20210727</enddate><creator>Yeh, Chi-Tai</creator><creator>Chen, Tzu-Tao</creator><creator>Satriyo, Pamungkas Bagus</creator><creator>Wang, Chun-Hua</creator><creator>Wu, Alexander T. 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H.</au><au>Chao, Tsu-Yi</au><au>Lee, Kang-Yun</au><au>Hsiao, Michael</au><au>Wang, Liang-Shun</au><au>Kuo, Kuang-Tai</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bruton’s tyrosine kinase (BTK) mediates resistance to EGFR inhibition in non-small-cell lung carcinoma</atitle><jtitle>Oncogenesis (New York, NY)</jtitle><stitle>Oncogenesis</stitle><stitle>ONCOGENESIS</stitle><date>2021-07-27</date><risdate>2021</risdate><volume>10</volume><issue>7</issue><spage>56</spage><epage>56</epage><pages>56-56</pages><artnum>56</artnum><issn>2157-9024</issn><eissn>2157-9024</eissn><abstract>Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are current standard of care for patients with EGFR mutation and metastatic non-small-cell lung carcinoma (NSCLC), but most patients using EGFR TKIs acquire resistance later. So, overcoming resistance of EGFR TKIs has become an important issue in the treatment of NSCLC. Previously, therapeutics targeting Bruton’s tyrosine kinase (BTK) have been successful in treating several hematologic malignancies. However, the role of BTK in NSCLC is still unknown. In this study, by examining surgical specimens from 80 NSCLC patients and their clinicopathologic parameters, we found significant correlation between high BTK expression and tumor differentiation, p-stage, lymph node metastatic status, maximum tumor size, and poor prognosis of patients. Using two NSCLC cell lines A540 and PC9, we demonstrated that BTK
pos
cells exhibited more stemness (OCT4, SOX2) and EMT (E-Cadherin, Slug) markers than BTK
neg
cells. Knockdown of BTK sensitized the NSCLC cells to Gefitinib. Meanwhile, the second-generation BTK inhibitor Acalabrutinib effectively suppressed SOX2, STAT3/JAK2/Akt axis and potentiated the anti-proliferative effect of Gefitinib and Osimertinib in NSCLC cells, including the T790M H1975 cells. Furthermore, Acalabrutinib and Osimertinib combination exhibited significant tumor growth inhibition of H1975-derived tumors in vivo. Our findings suggested that BTK mediates stemness and EMT properties, and inhibition of BTK potentiates the effect of Gefitinib and Osimertinib in NSCLC cells resistant to TKI. This implies a new approach to treat the NSCLC patients with resistance to previous TKI treatment.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34315851</pmid><doi>10.1038/s41389-021-00345-8</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0003-2754-2283</orcidid><orcidid>https://orcid.org/0000-0002-0178-6530</orcidid><orcidid>https://orcid.org/0000-0001-8529-9213</orcidid><orcidid>https://orcid.org/0000-0001-9544-3119</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | 13 13/100 13/109 13/2 13/31 13/51 13/89 631/154/53/2422 631/67/1612/1350 AKT protein Apoptosis Bruton's tyrosine kinase Cell Biology E-cadherin Epidermal growth factor Epidermal growth factor receptors Gefitinib Human Genetics Internal Medicine Janus kinase 2 Life Sciences & Biomedicine Lung cancer Lung carcinoma Lymph nodes Medicine Medicine & Public Health Metastases Metastasis Non-small cell lung carcinoma Oct-4 protein Oncology Patients Protein-tyrosine kinase Science & Technology Stat3 protein Targeted cancer therapy Tumors |
title | Bruton’s tyrosine kinase (BTK) mediates resistance to EGFR inhibition in non-small-cell lung carcinoma |
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