Bosutinib inhibits migration and invasion via ACK1 in KRAS mutant non-small cell lung cancer
The advent of effective targeted therapeutics has led to increasing emphasis on precise biomarkers for accurate patient stratification. Here, we describe the role of ACK1, a non-receptor tyrosine kinase in abrogating migration and invasion in KRAS mutant lung adenocarcinoma. Bosutinib, which inhibit...
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| Veröffentlicht in: | Molecular cancer 2014-01, Vol.13 (1), p.13-13, Article 13 |
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| creator | Tan, Daniel S W Haaland, Benjamin Gan, Jia Min Tham, Su Chin Sinha, Indrajit Tan, Eng Huat Lim, Kiat Hon Takano, Angela Krisna, Sai Sakktee Thu, Minn Minn Myint Liew, Hoe Peng Ullrich, Axel Lim, Wan-Teck Chua, Boon Tin |
| description | The advent of effective targeted therapeutics has led to increasing emphasis on precise biomarkers for accurate patient stratification. Here, we describe the role of ACK1, a non-receptor tyrosine kinase in abrogating migration and invasion in KRAS mutant lung adenocarcinoma. Bosutinib, which inhibits ACK1 at 2.7 nM IC50, was found to inhibit cell migration and invasion but not viability in a panel of non-small cell lung cancer (NSCLC) cell lines. Knockdown of ACK1 abrogated bosutinib-induced inhibition of cell migration and invasion specifically in KRAS mutant cells. This finding was further confirmed in an in vivo zebrafish metastatic model. Tissue microarray data on 210 Singaporean lung adenocarcinomas indicate that cytoplasmic ACK1 was significantly over-expressed relative to paired adjacent non-tumor tissue. Interestingly, ACK1 expression in "normal" tissue adjacent to tumour, but not tumour, was independently associated with poor overall and relapse-free survival. In conclusion, inhibition of ACK1 with bosutinib attenuates migration and invasion in the context of KRAS mutant NSCLC and may fulfil a therapeutic niche through combinatorial treatment approaches. |
| doi_str_mv | 10.1186/1476-4598-13-13 |
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Here, we describe the role of ACK1, a non-receptor tyrosine kinase in abrogating migration and invasion in KRAS mutant lung adenocarcinoma. Bosutinib, which inhibits ACK1 at 2.7 nM IC50, was found to inhibit cell migration and invasion but not viability in a panel of non-small cell lung cancer (NSCLC) cell lines. Knockdown of ACK1 abrogated bosutinib-induced inhibition of cell migration and invasion specifically in KRAS mutant cells. This finding was further confirmed in an in vivo zebrafish metastatic model. Tissue microarray data on 210 Singaporean lung adenocarcinomas indicate that cytoplasmic ACK1 was significantly over-expressed relative to paired adjacent non-tumor tissue. Interestingly, ACK1 expression in "normal" tissue adjacent to tumour, but not tumour, was independently associated with poor overall and relapse-free survival. In conclusion, inhibition of ACK1 with bosutinib attenuates migration and invasion in the context of KRAS mutant NSCLC and may fulfil a therapeutic niche through combinatorial treatment approaches.</description><identifier>ISSN: 1476-4598</identifier><identifier>EISSN: 1476-4598</identifier><identifier>DOI: 10.1186/1476-4598-13-13</identifier><identifier>PMID: 24461128</identifier><language>eng</language><publisher>England: BioMed Central</publisher><subject>Aniline Compounds - pharmacology ; Animals ; Antineoplastic Agents - pharmacology ; Apoptosis ; Biomedical research ; Blotting, Western ; Carcinoma, Non-Small-Cell Lung - genetics ; Carcinoma, Non-Small-Cell Lung - metabolism ; Carcinoma, Non-Small-Cell Lung - pathology ; Cell adhesion & migration ; Cell Line, Tumor ; Cell Movement - drug effects ; Experiments ; Gene Knockdown Techniques ; Humans ; Kinases ; Lung cancer ; Lung Neoplasms - genetics ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Mutation ; Neoplasm Invasiveness - pathology ; Nitriles - pharmacology ; Phosphorylation ; Protein-Tyrosine Kinases - metabolism ; Proteins ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins p21(ras) ; Quinolines - pharmacology ; ras Proteins - genetics ; Real-Time Polymerase Chain Reaction ; Science ; Statistical analysis ; Tissue Array Analysis ; Xenograft Model Antitumor Assays ; Zebrafish</subject><ispartof>Molecular cancer, 2014-01, Vol.13 (1), p.13-13, Article 13</ispartof><rights>2014 Tan et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.</rights><rights>Copyright © 2014 Tan et al.; licensee BioMed Central Ltd. 2014 Tan et al.; licensee BioMed Central Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b480t-36259ba963a000f5b9af7e4e05c509afbfd95a388be779ed391214fb234d47fb3</citedby><cites>FETCH-LOGICAL-b480t-36259ba963a000f5b9af7e4e05c509afbfd95a388be779ed391214fb234d47fb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930897/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930897/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,27911,27912,53778,53780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24461128$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tan, Daniel S W</creatorcontrib><creatorcontrib>Haaland, Benjamin</creatorcontrib><creatorcontrib>Gan, Jia Min</creatorcontrib><creatorcontrib>Tham, Su Chin</creatorcontrib><creatorcontrib>Sinha, Indrajit</creatorcontrib><creatorcontrib>Tan, Eng Huat</creatorcontrib><creatorcontrib>Lim, Kiat Hon</creatorcontrib><creatorcontrib>Takano, Angela</creatorcontrib><creatorcontrib>Krisna, Sai Sakktee</creatorcontrib><creatorcontrib>Thu, Minn Minn Myint</creatorcontrib><creatorcontrib>Liew, Hoe Peng</creatorcontrib><creatorcontrib>Ullrich, Axel</creatorcontrib><creatorcontrib>Lim, Wan-Teck</creatorcontrib><creatorcontrib>Chua, Boon Tin</creatorcontrib><title>Bosutinib inhibits migration and invasion via ACK1 in KRAS mutant non-small cell lung cancer</title><title>Molecular cancer</title><addtitle>Mol Cancer</addtitle><description>The advent of effective targeted therapeutics has led to increasing emphasis on precise biomarkers for accurate patient stratification. Here, we describe the role of ACK1, a non-receptor tyrosine kinase in abrogating migration and invasion in KRAS mutant lung adenocarcinoma. Bosutinib, which inhibits ACK1 at 2.7 nM IC50, was found to inhibit cell migration and invasion but not viability in a panel of non-small cell lung cancer (NSCLC) cell lines. Knockdown of ACK1 abrogated bosutinib-induced inhibition of cell migration and invasion specifically in KRAS mutant cells. This finding was further confirmed in an in vivo zebrafish metastatic model. Tissue microarray data on 210 Singaporean lung adenocarcinomas indicate that cytoplasmic ACK1 was significantly over-expressed relative to paired adjacent non-tumor tissue. Interestingly, ACK1 expression in "normal" tissue adjacent to tumour, but not tumour, was independently associated with poor overall and relapse-free survival. In conclusion, inhibition of ACK1 with bosutinib attenuates migration and invasion in the context of KRAS mutant NSCLC and may fulfil a therapeutic niche through combinatorial treatment approaches.</description><subject>Aniline Compounds - pharmacology</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Biomedical research</subject><subject>Blotting, Western</subject><subject>Carcinoma, Non-Small-Cell Lung - genetics</subject><subject>Carcinoma, Non-Small-Cell Lung - metabolism</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Cell adhesion & migration</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - drug effects</subject><subject>Experiments</subject><subject>Gene Knockdown Techniques</subject><subject>Humans</subject><subject>Kinases</subject><subject>Lung cancer</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - pathology</subject><subject>Mutation</subject><subject>Neoplasm Invasiveness - pathology</subject><subject>Nitriles - pharmacology</subject><subject>Phosphorylation</subject><subject>Protein-Tyrosine Kinases - metabolism</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins p21(ras)</subject><subject>Quinolines - pharmacology</subject><subject>ras Proteins - genetics</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Science</subject><subject>Statistical analysis</subject><subject>Tissue Array Analysis</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Zebrafish</subject><issn>1476-4598</issn><issn>1476-4598</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNp1UU1LxDAUDKL4ffYmAS9eqkmTNslFWBe_UBD8uAkhadM10iaatAv-e1NWFxWFR_LevGEY5gGwh9ERxrw8xpSVGS0EzzBJtQI2l8jqt34DbMX4ghBmnNF1sJFTWmKc803wdOrj0FtnNbTu2WrbR9jZWVC99Q4qVyd4ruI4zK2Ck-k1Tgi8vpvcw27oleuh8y6LnWpbWJn0tIObwUq5yoQdsNaoNprdz38bPJ6fPUwvs5vbi6vp5CbTlKM-I2VeCK1ESRRCqCm0UA0z1KCiKlDqdVOLQhHOtWFMmJoInGPa6JzQmrJGk21wstB9HXRn6sq4PqhWvgbbqfAuvbLy58bZZznzc0kEQVywJHC6ENDW_yPwc1P5To7pyjFdiUmqJHL46SL4t8HEXnY2jpEoZ_wQJS4Q5iRnuUjUg1_UFz8ElzIaWUiUCBc0sY4XrCr4GINploYwkuP5_7Cw_z2IJf_r3uQDNPOrVA</recordid><startdate>20140124</startdate><enddate>20140124</enddate><creator>Tan, Daniel S W</creator><creator>Haaland, Benjamin</creator><creator>Gan, Jia Min</creator><creator>Tham, Su Chin</creator><creator>Sinha, Indrajit</creator><creator>Tan, Eng Huat</creator><creator>Lim, Kiat Hon</creator><creator>Takano, Angela</creator><creator>Krisna, Sai Sakktee</creator><creator>Thu, Minn Minn Myint</creator><creator>Liew, Hoe Peng</creator><creator>Ullrich, Axel</creator><creator>Lim, Wan-Teck</creator><creator>Chua, Boon Tin</creator><general>BioMed Central</general><general>BioMed Central Ltd</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>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20140124</creationdate><title>Bosutinib inhibits migration and invasion via ACK1 in KRAS mutant non-small cell lung cancer</title><author>Tan, Daniel S W ; Haaland, Benjamin ; Gan, Jia Min ; Tham, Su Chin ; Sinha, Indrajit ; Tan, Eng Huat ; Lim, Kiat Hon ; Takano, Angela ; Krisna, Sai Sakktee ; Thu, Minn Minn Myint ; Liew, Hoe Peng ; Ullrich, Axel ; Lim, Wan-Teck ; Chua, Boon Tin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b480t-36259ba963a000f5b9af7e4e05c509afbfd95a388be779ed391214fb234d47fb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Aniline Compounds - pharmacology</topic><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Biomedical research</topic><topic>Blotting, Western</topic><topic>Carcinoma, Non-Small-Cell Lung - genetics</topic><topic>Carcinoma, Non-Small-Cell Lung - metabolism</topic><topic>Carcinoma, Non-Small-Cell Lung - pathology</topic><topic>Cell adhesion & migration</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement - drug effects</topic><topic>Experiments</topic><topic>Gene Knockdown Techniques</topic><topic>Humans</topic><topic>Kinases</topic><topic>Lung cancer</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - metabolism</topic><topic>Lung Neoplasms - pathology</topic><topic>Mutation</topic><topic>Neoplasm Invasiveness - pathology</topic><topic>Nitriles - pharmacology</topic><topic>Phosphorylation</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins - genetics</topic><topic>Proto-Oncogene Proteins p21(ras)</topic><topic>Quinolines - pharmacology</topic><topic>ras Proteins - genetics</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Science</topic><topic>Statistical analysis</topic><topic>Tissue Array Analysis</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Zebrafish</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tan, Daniel S W</creatorcontrib><creatorcontrib>Haaland, Benjamin</creatorcontrib><creatorcontrib>Gan, Jia Min</creatorcontrib><creatorcontrib>Tham, Su Chin</creatorcontrib><creatorcontrib>Sinha, Indrajit</creatorcontrib><creatorcontrib>Tan, Eng Huat</creatorcontrib><creatorcontrib>Lim, Kiat Hon</creatorcontrib><creatorcontrib>Takano, Angela</creatorcontrib><creatorcontrib>Krisna, Sai Sakktee</creatorcontrib><creatorcontrib>Thu, Minn Minn Myint</creatorcontrib><creatorcontrib>Liew, Hoe Peng</creatorcontrib><creatorcontrib>Ullrich, Axel</creatorcontrib><creatorcontrib>Lim, Wan-Teck</creatorcontrib><creatorcontrib>Chua, Boon Tin</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>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</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>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tan, Daniel S W</au><au>Haaland, Benjamin</au><au>Gan, Jia Min</au><au>Tham, Su Chin</au><au>Sinha, Indrajit</au><au>Tan, Eng Huat</au><au>Lim, Kiat Hon</au><au>Takano, Angela</au><au>Krisna, Sai Sakktee</au><au>Thu, Minn Minn Myint</au><au>Liew, Hoe Peng</au><au>Ullrich, Axel</au><au>Lim, Wan-Teck</au><au>Chua, Boon Tin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bosutinib inhibits migration and invasion via ACK1 in KRAS mutant non-small cell lung cancer</atitle><jtitle>Molecular cancer</jtitle><addtitle>Mol Cancer</addtitle><date>2014-01-24</date><risdate>2014</risdate><volume>13</volume><issue>1</issue><spage>13</spage><epage>13</epage><pages>13-13</pages><artnum>13</artnum><issn>1476-4598</issn><eissn>1476-4598</eissn><abstract>The advent of effective targeted therapeutics has led to increasing emphasis on precise biomarkers for accurate patient stratification. Here, we describe the role of ACK1, a non-receptor tyrosine kinase in abrogating migration and invasion in KRAS mutant lung adenocarcinoma. Bosutinib, which inhibits ACK1 at 2.7 nM IC50, was found to inhibit cell migration and invasion but not viability in a panel of non-small cell lung cancer (NSCLC) cell lines. Knockdown of ACK1 abrogated bosutinib-induced inhibition of cell migration and invasion specifically in KRAS mutant cells. This finding was further confirmed in an in vivo zebrafish metastatic model. Tissue microarray data on 210 Singaporean lung adenocarcinomas indicate that cytoplasmic ACK1 was significantly over-expressed relative to paired adjacent non-tumor tissue. Interestingly, ACK1 expression in "normal" tissue adjacent to tumour, but not tumour, was independently associated with poor overall and relapse-free survival. In conclusion, inhibition of ACK1 with bosutinib attenuates migration and invasion in the context of KRAS mutant NSCLC and may fulfil a therapeutic niche through combinatorial treatment approaches.</abstract><cop>England</cop><pub>BioMed Central</pub><pmid>24461128</pmid><doi>10.1186/1476-4598-13-13</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aniline Compounds - pharmacology Animals Antineoplastic Agents - pharmacology Apoptosis Biomedical research Blotting, Western Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - pathology Cell adhesion & migration Cell Line, Tumor Cell Movement - drug effects Experiments Gene Knockdown Techniques Humans Kinases Lung cancer Lung Neoplasms - genetics Lung Neoplasms - metabolism Lung Neoplasms - pathology Mutation Neoplasm Invasiveness - pathology Nitriles - pharmacology Phosphorylation Protein-Tyrosine Kinases - metabolism Proteins Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins p21(ras) Quinolines - pharmacology ras Proteins - genetics Real-Time Polymerase Chain Reaction Science Statistical analysis Tissue Array Analysis Xenograft Model Antitumor Assays Zebrafish |
| title | Bosutinib inhibits migration and invasion via ACK1 in KRAS mutant non-small cell lung cancer |
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