RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas
Non-small cell lung cancer (NSCLC) often expresses mutant KRAS together with tumor-associated mutations of the CDKN2A locus, which are associated with aggressive, therapy-resistant tumors. Here, we unravel specific requirements for the maintenance of NSCLC that carries this genotype. We establish th...
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| Veröffentlicht in: | Cancer discovery 2013-04, Vol.3 (4), p.444-457 |
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| creator | Konstantinidou, Georgia Ramadori, Giorgio Torti, Francesca Kangasniemi, Kim Ramirez, Rachel E Cai, Yiran Behrens, Carmen Dellinger, Michael T Brekken, Rolf A Wistuba, Ignacio I Heguy, Adriana Teruya-Feldstein, Julie Scaglioni, Pier Paolo |
| description | Non-small cell lung cancer (NSCLC) often expresses mutant KRAS together with tumor-associated mutations of the CDKN2A locus, which are associated with aggressive, therapy-resistant tumors. Here, we unravel specific requirements for the maintenance of NSCLC that carries this genotype. We establish that the extracellular signal-regulated kinase (ERK)/RHOA/focal adhesion kinase (FAK) network is deregulated in high-grade lung tumors. Suppression of RHOA or FAK induces cell death selectively in mutant KRAS;INK4A/ARF-deficient lung cancer cells. Furthermore, pharmacologic inhibition of FAK caused tumor regression specifically in the high-grade lung cancer that developed in mutant Kras;Cdkn2a-null mice. These findings provide a rationale for the rapid implementation of genotype-specific targeted therapies using FAK inhibitors in patients with cancer.
Targeted therapies are effective for only a small fraction of patients with cancer. We report that FAK inhibitors exert potent antitumor effects in NSCLCs that express mutant KRAS in association with INK4A/ARF deficiency. These results reveal a novel genotype-specific vulnerability of cancer cells that can be exploited for therapeutic purposes. |
| doi_str_mv | 10.1158/2159-8290.CD-12-0388 |
| format | Article |
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Targeted therapies are effective for only a small fraction of patients with cancer. We report that FAK inhibitors exert potent antitumor effects in NSCLCs that express mutant KRAS in association with INK4A/ARF deficiency. These results reveal a novel genotype-specific vulnerability of cancer cells that can be exploited for therapeutic purposes.</description><identifier>ISSN: 2159-8274</identifier><identifier>EISSN: 2159-8290</identifier><identifier>DOI: 10.1158/2159-8290.CD-12-0388</identifier><identifier>PMID: 23358651</identifier><language>eng</language><publisher>United States</publisher><subject>Adenocarcinoma - drug therapy ; Adenocarcinoma - genetics ; Adenocarcinoma - metabolism ; Adenocarcinoma of Lung ; Animals ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Non-Small-Cell Lung - genetics ; Carcinoma, Non-Small-Cell Lung - metabolism ; Cell Line, Tumor ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Female ; Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors ; Focal Adhesion Protein-Tyrosine Kinases - metabolism ; Genes, ras - genetics ; Humans ; Lung Neoplasms - drug therapy ; Lung Neoplasms - genetics ; Lung Neoplasms - metabolism ; Mice ; Mice, Nude ; Mice, Transgenic ; Protein Kinase Inhibitors - therapeutic use ; rhoA GTP-Binding Protein - metabolism ; Signal Transduction ; Xenograft Model Antitumor Assays</subject><ispartof>Cancer discovery, 2013-04, Vol.3 (4), p.444-457</ispartof><rights>2013 AACR.</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c404t-99fb8c0c4e0939937569fe314bfadaab4ef64746365419d14367e9494c17019b3</citedby><cites>FETCH-LOGICAL-c404t-99fb8c0c4e0939937569fe314bfadaab4ef64746365419d14367e9494c17019b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23358651$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Konstantinidou, Georgia</creatorcontrib><creatorcontrib>Ramadori, Giorgio</creatorcontrib><creatorcontrib>Torti, Francesca</creatorcontrib><creatorcontrib>Kangasniemi, Kim</creatorcontrib><creatorcontrib>Ramirez, Rachel E</creatorcontrib><creatorcontrib>Cai, Yiran</creatorcontrib><creatorcontrib>Behrens, Carmen</creatorcontrib><creatorcontrib>Dellinger, Michael T</creatorcontrib><creatorcontrib>Brekken, Rolf A</creatorcontrib><creatorcontrib>Wistuba, Ignacio I</creatorcontrib><creatorcontrib>Heguy, Adriana</creatorcontrib><creatorcontrib>Teruya-Feldstein, Julie</creatorcontrib><creatorcontrib>Scaglioni, Pier Paolo</creatorcontrib><title>RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas</title><title>Cancer discovery</title><addtitle>Cancer Discov</addtitle><description>Non-small cell lung cancer (NSCLC) often expresses mutant KRAS together with tumor-associated mutations of the CDKN2A locus, which are associated with aggressive, therapy-resistant tumors. Here, we unravel specific requirements for the maintenance of NSCLC that carries this genotype. We establish that the extracellular signal-regulated kinase (ERK)/RHOA/focal adhesion kinase (FAK) network is deregulated in high-grade lung tumors. Suppression of RHOA or FAK induces cell death selectively in mutant KRAS;INK4A/ARF-deficient lung cancer cells. Furthermore, pharmacologic inhibition of FAK caused tumor regression specifically in the high-grade lung cancer that developed in mutant Kras;Cdkn2a-null mice. These findings provide a rationale for the rapid implementation of genotype-specific targeted therapies using FAK inhibitors in patients with cancer.
Targeted therapies are effective for only a small fraction of patients with cancer. We report that FAK inhibitors exert potent antitumor effects in NSCLCs that express mutant KRAS in association with INK4A/ARF deficiency. These results reveal a novel genotype-specific vulnerability of cancer cells that can be exploited for therapeutic purposes.</description><subject>Adenocarcinoma - drug therapy</subject><subject>Adenocarcinoma - genetics</subject><subject>Adenocarcinoma - metabolism</subject><subject>Adenocarcinoma of Lung</subject><subject>Animals</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Carcinoma, Non-Small-Cell Lung - genetics</subject><subject>Carcinoma, Non-Small-Cell Lung - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Female</subject><subject>Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Focal Adhesion Protein-Tyrosine Kinases - metabolism</subject><subject>Genes, ras - genetics</subject><subject>Humans</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - metabolism</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Mice, Transgenic</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>rhoA GTP-Binding Protein - metabolism</subject><subject>Signal Transduction</subject><subject>Xenograft Model Antitumor Assays</subject><issn>2159-8274</issn><issn>2159-8290</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kFFPwjAQxxujEYJ8A2P66MuwXdttfSQgYiAhQX00TdfdsGbroGVGv71bUO7lLnf_-1_uh9AtJRNKRfYQUyGjLJZkMptHNI4Iy7ILNDy3L891ygdoHMIn6YJLLkh6jQYxYyJLBB2i9-1yM40W0xW2AWvs4dBaDwUOdud0Zd0O6-9uUjYeHz8A19q6IzjtDOCmxKvt9CUqvP0Ch6u2FxfgGqO9sa6pdbhBV6WuAoz_8gi9LR5fZ8tovXl6nk3XkeGEHyMpyzwzxHAgkknJUpHIEhjleakLrXMOZcJTnrBEcCoLylmSguy-MTQlVOZshO5PvnvfHFoIR1XbYKCqtIOmDYoyIToDSWUn5Sep8U0IHkq197bW_kdRonq2qgeneohqNlc0Vj3bbu3u70Kb11Ccl_5Jsl8LZ3Lu</recordid><startdate>201304</startdate><enddate>201304</enddate><creator>Konstantinidou, Georgia</creator><creator>Ramadori, Giorgio</creator><creator>Torti, Francesca</creator><creator>Kangasniemi, Kim</creator><creator>Ramirez, Rachel E</creator><creator>Cai, Yiran</creator><creator>Behrens, Carmen</creator><creator>Dellinger, Michael T</creator><creator>Brekken, Rolf A</creator><creator>Wistuba, Ignacio I</creator><creator>Heguy, Adriana</creator><creator>Teruya-Feldstein, Julie</creator><creator>Scaglioni, Pier Paolo</creator><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>7X8</scope></search><sort><creationdate>201304</creationdate><title>RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas</title><author>Konstantinidou, Georgia ; Ramadori, Giorgio ; Torti, Francesca ; Kangasniemi, Kim ; Ramirez, Rachel E ; Cai, Yiran ; Behrens, Carmen ; Dellinger, Michael T ; Brekken, Rolf A ; Wistuba, Ignacio I ; Heguy, Adriana ; Teruya-Feldstein, Julie ; Scaglioni, Pier Paolo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c404t-99fb8c0c4e0939937569fe314bfadaab4ef64746365419d14367e9494c17019b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adenocarcinoma - drug therapy</topic><topic>Adenocarcinoma - genetics</topic><topic>Adenocarcinoma - metabolism</topic><topic>Adenocarcinoma of Lung</topic><topic>Animals</topic><topic>Carcinoma, Non-Small-Cell Lung - drug therapy</topic><topic>Carcinoma, Non-Small-Cell Lung - genetics</topic><topic>Carcinoma, Non-Small-Cell Lung - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>Female</topic><topic>Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Focal Adhesion Protein-Tyrosine Kinases - metabolism</topic><topic>Genes, ras - genetics</topic><topic>Humans</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - metabolism</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Mice, Transgenic</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>rhoA GTP-Binding Protein - metabolism</topic><topic>Signal Transduction</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>online_resources</toplevel><creatorcontrib>Konstantinidou, Georgia</creatorcontrib><creatorcontrib>Ramadori, Giorgio</creatorcontrib><creatorcontrib>Torti, Francesca</creatorcontrib><creatorcontrib>Kangasniemi, Kim</creatorcontrib><creatorcontrib>Ramirez, Rachel E</creatorcontrib><creatorcontrib>Cai, Yiran</creatorcontrib><creatorcontrib>Behrens, Carmen</creatorcontrib><creatorcontrib>Dellinger, Michael T</creatorcontrib><creatorcontrib>Brekken, Rolf A</creatorcontrib><creatorcontrib>Wistuba, Ignacio I</creatorcontrib><creatorcontrib>Heguy, Adriana</creatorcontrib><creatorcontrib>Teruya-Feldstein, Julie</creatorcontrib><creatorcontrib>Scaglioni, Pier Paolo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer discovery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Konstantinidou, Georgia</au><au>Ramadori, Giorgio</au><au>Torti, Francesca</au><au>Kangasniemi, Kim</au><au>Ramirez, Rachel E</au><au>Cai, Yiran</au><au>Behrens, Carmen</au><au>Dellinger, Michael T</au><au>Brekken, Rolf A</au><au>Wistuba, Ignacio I</au><au>Heguy, Adriana</au><au>Teruya-Feldstein, Julie</au><au>Scaglioni, Pier Paolo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas</atitle><jtitle>Cancer discovery</jtitle><addtitle>Cancer Discov</addtitle><date>2013-04</date><risdate>2013</risdate><volume>3</volume><issue>4</issue><spage>444</spage><epage>457</epage><pages>444-457</pages><issn>2159-8274</issn><eissn>2159-8290</eissn><abstract>Non-small cell lung cancer (NSCLC) often expresses mutant KRAS together with tumor-associated mutations of the CDKN2A locus, which are associated with aggressive, therapy-resistant tumors. Here, we unravel specific requirements for the maintenance of NSCLC that carries this genotype. We establish that the extracellular signal-regulated kinase (ERK)/RHOA/focal adhesion kinase (FAK) network is deregulated in high-grade lung tumors. Suppression of RHOA or FAK induces cell death selectively in mutant KRAS;INK4A/ARF-deficient lung cancer cells. Furthermore, pharmacologic inhibition of FAK caused tumor regression specifically in the high-grade lung cancer that developed in mutant Kras;Cdkn2a-null mice. These findings provide a rationale for the rapid implementation of genotype-specific targeted therapies using FAK inhibitors in patients with cancer.
Targeted therapies are effective for only a small fraction of patients with cancer. We report that FAK inhibitors exert potent antitumor effects in NSCLCs that express mutant KRAS in association with INK4A/ARF deficiency. These results reveal a novel genotype-specific vulnerability of cancer cells that can be exploited for therapeutic purposes.</abstract><cop>United States</cop><pmid>23358651</pmid><doi>10.1158/2159-8290.CD-12-0388</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Adenocarcinoma - drug therapy Adenocarcinoma - genetics Adenocarcinoma - metabolism Adenocarcinoma of Lung Animals Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - metabolism Cell Line, Tumor Extracellular Signal-Regulated MAP Kinases - metabolism Female Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors Focal Adhesion Protein-Tyrosine Kinases - metabolism Genes, ras - genetics Humans Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - metabolism Mice Mice, Nude Mice, Transgenic Protein Kinase Inhibitors - therapeutic use rhoA GTP-Binding Protein - metabolism Signal Transduction Xenograft Model Antitumor Assays |
| title | RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas |
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