The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma
New targets for Ewing sarcoma (ES) patients are urgently needed. Therefore, we investigated the expression and genetic aberrations of the oncogenic receptor tyrosine kinase (RTK) AXL in ES and determined the efficacy of AXL targeting on cell viability and migration. First, AXL and Gas6 (ligand) mRNA...
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| Veröffentlicht in: | Oncotarget 2014-12, Vol.5 (24), p.12753-12768 |
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| creator | Fleuren, Emmy D G Hillebrandt-Roeffen, Melissa H S Flucke, Uta E Te Loo, D Maroeska W M Boerman, Otto C van der Graaf, Winette T A Versleijen-Jonkers, Yvonne M H |
| description | New targets for Ewing sarcoma (ES) patients are urgently needed. Therefore, we investigated the expression and genetic aberrations of the oncogenic receptor tyrosine kinase (RTK) AXL in ES and determined the efficacy of AXL targeting on cell viability and migration. First, AXL and Gas6 (ligand) mRNA expression was determined by RT-PCR on 29 ES samples. Low, medium and high AXL mRNA expression was observed in 31% (n = 9), 48% (n = 14) and 21% (n = 6) of samples. Gas6 was abundantly present in all specimens. We next tested AXL protein expression immunohistochemically in 36 tumors (primary, post-chemotherapy, metastasized and relapsed samples) from 25 ES patients. Low, medium and high AXL protein expression was observed in 17% (n = 6), 19% (n = 7) and 36% (n = 13) of samples. In primary tumors (n = 15), high AXL expression correlated significantly with a worse overall survival compared to patients with lower expression (61 vs. 194 months, p = 0.026). No genetic aberrations were detected in the AXL RTK domain (n = 29). The AXL-inhibitor BGB324 affected viability (IC50 0.79-2.13 μmol/L) and migratory potential of all tested ES cell lines in vitro (n = 5-6). BGB324 chemosensitized chemotherapy-resistant ES-4 cells to vincristine and doxorubicin. These data suggest that AXL is a potential novel, druggable therapeutic target in ES. |
| doi_str_mv | 10.18632/oncotarget.2648 |
| format | Article |
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Therefore, we investigated the expression and genetic aberrations of the oncogenic receptor tyrosine kinase (RTK) AXL in ES and determined the efficacy of AXL targeting on cell viability and migration. First, AXL and Gas6 (ligand) mRNA expression was determined by RT-PCR on 29 ES samples. Low, medium and high AXL mRNA expression was observed in 31% (n = 9), 48% (n = 14) and 21% (n = 6) of samples. Gas6 was abundantly present in all specimens. We next tested AXL protein expression immunohistochemically in 36 tumors (primary, post-chemotherapy, metastasized and relapsed samples) from 25 ES patients. Low, medium and high AXL protein expression was observed in 17% (n = 6), 19% (n = 7) and 36% (n = 13) of samples. In primary tumors (n = 15), high AXL expression correlated significantly with a worse overall survival compared to patients with lower expression (61 vs. 194 months, p = 0.026). No genetic aberrations were detected in the AXL RTK domain (n = 29). The AXL-inhibitor BGB324 affected viability (IC50 0.79-2.13 μmol/L) and migratory potential of all tested ES cell lines in vitro (n = 5-6). BGB324 chemosensitized chemotherapy-resistant ES-4 cells to vincristine and doxorubicin. These data suggest that AXL is a potential novel, druggable therapeutic target in ES.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.2648</identifier><identifier>PMID: 25528764</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Adolescent ; Adult ; Benzocycloheptenes - pharmacology ; Cell Survival - drug effects ; Child ; Child, Preschool ; Female ; Humans ; In Vitro Techniques ; Intercellular Signaling Peptides and Proteins - biosynthesis ; Intercellular Signaling Peptides and Proteins - genetics ; Male ; Middle Aged ; Prognosis ; Protein Kinase Inhibitors - pharmacology ; Proto-Oncogene Proteins - antagonists & inhibitors ; Proto-Oncogene Proteins - biosynthesis ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - metabolism ; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors ; Receptor Protein-Tyrosine Kinases - biosynthesis ; Receptor Protein-Tyrosine Kinases - genetics ; Receptor Protein-Tyrosine Kinases - metabolism ; Research Paper ; RNA, Messenger - biosynthesis ; RNA, Messenger - genetics ; Sarcoma, Ewing - drug therapy ; Sarcoma, Ewing - enzymology ; Triazoles - pharmacology ; Young Adult</subject><ispartof>Oncotarget, 2014-12, Vol.5 (24), p.12753-12768</ispartof><rights>Copyright: © 2014 Fleuren et al. 2014</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c462t-2e00ecaa7220594a2978f43c5ba0dfc04bd90ba7759557a58c11267d067461d53</citedby><cites>FETCH-LOGICAL-c462t-2e00ecaa7220594a2978f43c5ba0dfc04bd90ba7759557a58c11267d067461d53</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/PMC4350331/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350331/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25528764$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fleuren, Emmy D G</creatorcontrib><creatorcontrib>Hillebrandt-Roeffen, Melissa H S</creatorcontrib><creatorcontrib>Flucke, Uta E</creatorcontrib><creatorcontrib>Te Loo, D Maroeska W M</creatorcontrib><creatorcontrib>Boerman, Otto C</creatorcontrib><creatorcontrib>van der Graaf, Winette T A</creatorcontrib><creatorcontrib>Versleijen-Jonkers, Yvonne M H</creatorcontrib><title>The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>New targets for Ewing sarcoma (ES) patients are urgently needed. Therefore, we investigated the expression and genetic aberrations of the oncogenic receptor tyrosine kinase (RTK) AXL in ES and determined the efficacy of AXL targeting on cell viability and migration. First, AXL and Gas6 (ligand) mRNA expression was determined by RT-PCR on 29 ES samples. Low, medium and high AXL mRNA expression was observed in 31% (n = 9), 48% (n = 14) and 21% (n = 6) of samples. Gas6 was abundantly present in all specimens. We next tested AXL protein expression immunohistochemically in 36 tumors (primary, post-chemotherapy, metastasized and relapsed samples) from 25 ES patients. Low, medium and high AXL protein expression was observed in 17% (n = 6), 19% (n = 7) and 36% (n = 13) of samples. In primary tumors (n = 15), high AXL expression correlated significantly with a worse overall survival compared to patients with lower expression (61 vs. 194 months, p = 0.026). No genetic aberrations were detected in the AXL RTK domain (n = 29). The AXL-inhibitor BGB324 affected viability (IC50 0.79-2.13 μmol/L) and migratory potential of all tested ES cell lines in vitro (n = 5-6). BGB324 chemosensitized chemotherapy-resistant ES-4 cells to vincristine and doxorubicin. These data suggest that AXL is a potential novel, druggable therapeutic target in ES.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Benzocycloheptenes - pharmacology</subject><subject>Cell Survival - drug effects</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Female</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Intercellular Signaling Peptides and Proteins - biosynthesis</subject><subject>Intercellular Signaling Peptides and Proteins - genetics</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Prognosis</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Proto-Oncogene Proteins - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins - biosynthesis</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Receptor Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Receptor Protein-Tyrosine Kinases - biosynthesis</subject><subject>Receptor Protein-Tyrosine Kinases - genetics</subject><subject>Receptor Protein-Tyrosine Kinases - metabolism</subject><subject>Research Paper</subject><subject>RNA, Messenger - biosynthesis</subject><subject>RNA, Messenger - genetics</subject><subject>Sarcoma, Ewing - drug therapy</subject><subject>Sarcoma, Ewing - enzymology</subject><subject>Triazoles - pharmacology</subject><subject>Young Adult</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUUtLAzEQDqKoqHdPkqOXap6b3YugUh9Q8FLBW5jNZtvoNqlJqvTfu6v1lUuG-R4zzIfQMSVntCw4Ow_ehAxxZvMZK0S5hfZpJaoRk5Jv_6n30FFKz6R_UqiSVbtor2-zUhViH71M5xbH0FkcWnz5NMHgG5z7nvP4zeUYMJjs-mo9EAYgWmOXOUSc1zEk5y1-cR7SoJi72g3I1e0VZ2KwGL87P8MJogkLOEQ7LXTJHm3-A_R4M55e340mD7f315eTkREFyyNmCbEGQDFGZCWAVapsBTeyBtK0hoi6qUgNSslKSgWyNJSyQjWkUKKgjeQH6OLLd7mqF7Yx1ucInV5Gt4C41gGc_o94N9ez8KYFl4Rz2hucbgxieF3ZlPXCJWO7DrwNq6RpIZkgVJRlTyVfVNMfI0Xb_oyhRH_GpH9j0kNMveTk73o_gu9Q-AchVJEU</recordid><startdate>20141230</startdate><enddate>20141230</enddate><creator>Fleuren, Emmy D G</creator><creator>Hillebrandt-Roeffen, Melissa H S</creator><creator>Flucke, Uta E</creator><creator>Te Loo, D Maroeska W M</creator><creator>Boerman, Otto C</creator><creator>van der Graaf, Winette T A</creator><creator>Versleijen-Jonkers, Yvonne M H</creator><general>Impact Journals LLC</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20141230</creationdate><title>The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma</title><author>Fleuren, Emmy D G ; Hillebrandt-Roeffen, Melissa H S ; Flucke, Uta E ; Te Loo, D Maroeska W M ; Boerman, Otto C ; van der Graaf, Winette T A ; Versleijen-Jonkers, Yvonne M H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c462t-2e00ecaa7220594a2978f43c5ba0dfc04bd90ba7759557a58c11267d067461d53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Benzocycloheptenes - pharmacology</topic><topic>Cell Survival - drug effects</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Female</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Intercellular Signaling Peptides and Proteins - biosynthesis</topic><topic>Intercellular Signaling Peptides and Proteins - genetics</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Prognosis</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Proto-Oncogene Proteins - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins - biosynthesis</topic><topic>Proto-Oncogene Proteins - genetics</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Receptor Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Receptor Protein-Tyrosine Kinases - biosynthesis</topic><topic>Receptor Protein-Tyrosine Kinases - genetics</topic><topic>Receptor Protein-Tyrosine Kinases - metabolism</topic><topic>Research Paper</topic><topic>RNA, Messenger - biosynthesis</topic><topic>RNA, Messenger - genetics</topic><topic>Sarcoma, Ewing - drug therapy</topic><topic>Sarcoma, Ewing - enzymology</topic><topic>Triazoles - pharmacology</topic><topic>Young Adult</topic><toplevel>online_resources</toplevel><creatorcontrib>Fleuren, Emmy D G</creatorcontrib><creatorcontrib>Hillebrandt-Roeffen, Melissa H S</creatorcontrib><creatorcontrib>Flucke, Uta E</creatorcontrib><creatorcontrib>Te Loo, D Maroeska W M</creatorcontrib><creatorcontrib>Boerman, Otto C</creatorcontrib><creatorcontrib>van der Graaf, Winette T A</creatorcontrib><creatorcontrib>Versleijen-Jonkers, Yvonne M H</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fleuren, Emmy D G</au><au>Hillebrandt-Roeffen, Melissa H S</au><au>Flucke, Uta E</au><au>Te Loo, D Maroeska W M</au><au>Boerman, Otto C</au><au>van der Graaf, Winette T A</au><au>Versleijen-Jonkers, Yvonne M H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2014-12-30</date><risdate>2014</risdate><volume>5</volume><issue>24</issue><spage>12753</spage><epage>12768</epage><pages>12753-12768</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>New targets for Ewing sarcoma (ES) patients are urgently needed. Therefore, we investigated the expression and genetic aberrations of the oncogenic receptor tyrosine kinase (RTK) AXL in ES and determined the efficacy of AXL targeting on cell viability and migration. First, AXL and Gas6 (ligand) mRNA expression was determined by RT-PCR on 29 ES samples. Low, medium and high AXL mRNA expression was observed in 31% (n = 9), 48% (n = 14) and 21% (n = 6) of samples. Gas6 was abundantly present in all specimens. We next tested AXL protein expression immunohistochemically in 36 tumors (primary, post-chemotherapy, metastasized and relapsed samples) from 25 ES patients. Low, medium and high AXL protein expression was observed in 17% (n = 6), 19% (n = 7) and 36% (n = 13) of samples. In primary tumors (n = 15), high AXL expression correlated significantly with a worse overall survival compared to patients with lower expression (61 vs. 194 months, p = 0.026). No genetic aberrations were detected in the AXL RTK domain (n = 29). The AXL-inhibitor BGB324 affected viability (IC50 0.79-2.13 μmol/L) and migratory potential of all tested ES cell lines in vitro (n = 5-6). BGB324 chemosensitized chemotherapy-resistant ES-4 cells to vincristine and doxorubicin. These data suggest that AXL is a potential novel, druggable therapeutic target in ES.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>25528764</pmid><doi>10.18632/oncotarget.2648</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adolescent Adult Benzocycloheptenes - pharmacology Cell Survival - drug effects Child Child, Preschool Female Humans In Vitro Techniques Intercellular Signaling Peptides and Proteins - biosynthesis Intercellular Signaling Peptides and Proteins - genetics Male Middle Aged Prognosis Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins - antagonists & inhibitors Proto-Oncogene Proteins - biosynthesis Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Receptor Protein-Tyrosine Kinases - antagonists & inhibitors Receptor Protein-Tyrosine Kinases - biosynthesis Receptor Protein-Tyrosine Kinases - genetics Receptor Protein-Tyrosine Kinases - metabolism Research Paper RNA, Messenger - biosynthesis RNA, Messenger - genetics Sarcoma, Ewing - drug therapy Sarcoma, Ewing - enzymology Triazoles - pharmacology Young Adult |
| title | The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma |
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