Tie2-FGFR1 Interaction Induces Adaptive PI3K Inhibitor Resistance by Upregulating Aurora A/PLK1/CDK1 Signaling in Glioblastoma
PI3K-targeting therapy represents one of the most sought-after therapies for glioblastoma (GBM). Several small-molecule inhibitors have been evaluated in clinical trials, however, the emergence of resistance limits treatment potential. Here, we generated a patient-derived glioma sphere-forming cell...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2019-10, Vol.79 (19), p.5088-5101 |
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| creator | Li, Xiaolong Martinez-Ledesma, Emmanuel Zhang, Chen Gao, Feng Zheng, Siyuan Ding, Jie Wu, Shaofang Nguyen, Nghi Clifford, Stephan C Wen, Patrick Y Ligon, Keith L Yung, W K Alfred Koul, Dimpy |
| description | PI3K-targeting therapy represents one of the most sought-after therapies for glioblastoma (GBM). Several small-molecule inhibitors have been evaluated in clinical trials, however, the emergence of resistance limits treatment potential. Here, we generated a patient-derived glioma sphere-forming cell (GSC) xenograft model resistant to the PI3K-specific inhibitor BKM-120. Integrated RNA sequencing and high-throughput drug screening revealed that the Aurora A kinase (Aurora A)/Polo-like kinase 1 (PLK1)/cyclin-dependent kinase 1 (CDK1) signaling pathway was the main driver of PI3K inhibitor resistance in the resistant xenografts. Aurora kinase was upregulated and pCDK1 was downregulated in resistant tumors from both xenografts and tumor tissues from patients treated with the PI3K inhibitor. Mechanistically, the tyrosine kinase receptor Tie2 physically interacted with FGFR1, promoting STAT3 phosphorylation and binding to the
promoter, which increased Aurora A expression in resistant GSCs. Concurrent inhibition of Aurora A and PI3K signaling overcame PI3K inhibitor-induced resistance. This study offers a proof of concept to target PI3K and the collateral-activated pathway to improve GBM therapy. SIGNIFICANCE: These findings provide novel insights into the mechanisms of PI3K inhibitor resistance in glioblastoma. |
| doi_str_mv | 10.1158/0008-5472.CAN-19-0325 |
| format | Article |
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promoter, which increased Aurora A expression in resistant GSCs. Concurrent inhibition of Aurora A and PI3K signaling overcame PI3K inhibitor-induced resistance. This study offers a proof of concept to target PI3K and the collateral-activated pathway to improve GBM therapy. SIGNIFICANCE: These findings provide novel insights into the mechanisms of PI3K inhibitor resistance in glioblastoma.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-19-0325</identifier><identifier>PMID: 31416846</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Aurora Kinase A - metabolism ; CDC2 Protein Kinase - metabolism ; Cell Cycle Proteins - metabolism ; Drug Resistance, Neoplasm - physiology ; Glioblastoma - pathology ; Heterografts ; Humans ; Male ; Mice ; Mice, Nude ; Phosphatidylinositol 3-Kinases - metabolism ; Polo-Like Kinase 1 ; Protein Kinase Inhibitors - pharmacology ; Protein Serine-Threonine Kinases - metabolism ; Proto-Oncogene Proteins - metabolism ; Receptor, Fibroblast Growth Factor, Type 1 - metabolism ; Receptor, TIE-2 - metabolism ; Signal Transduction - physiology ; Up-Regulation</subject><ispartof>Cancer research (Chicago, Ill.), 2019-10, Vol.79 (19), p.5088-5101</ispartof><rights>2019 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-16065ed5ada460fa45a03113196527daed8dd8e4d0036d6dd82f91e80df428783</citedby><cites>FETCH-LOGICAL-c356t-16065ed5ada460fa45a03113196527daed8dd8e4d0036d6dd82f91e80df428783</cites><orcidid>0000-0002-1031-9424</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31416846$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Xiaolong</creatorcontrib><creatorcontrib>Martinez-Ledesma, Emmanuel</creatorcontrib><creatorcontrib>Zhang, Chen</creatorcontrib><creatorcontrib>Gao, Feng</creatorcontrib><creatorcontrib>Zheng, Siyuan</creatorcontrib><creatorcontrib>Ding, Jie</creatorcontrib><creatorcontrib>Wu, Shaofang</creatorcontrib><creatorcontrib>Nguyen, Nghi</creatorcontrib><creatorcontrib>Clifford, Stephan C</creatorcontrib><creatorcontrib>Wen, Patrick Y</creatorcontrib><creatorcontrib>Ligon, Keith L</creatorcontrib><creatorcontrib>Yung, W K Alfred</creatorcontrib><creatorcontrib>Koul, Dimpy</creatorcontrib><title>Tie2-FGFR1 Interaction Induces Adaptive PI3K Inhibitor Resistance by Upregulating Aurora A/PLK1/CDK1 Signaling in Glioblastoma</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>PI3K-targeting therapy represents one of the most sought-after therapies for glioblastoma (GBM). Several small-molecule inhibitors have been evaluated in clinical trials, however, the emergence of resistance limits treatment potential. Here, we generated a patient-derived glioma sphere-forming cell (GSC) xenograft model resistant to the PI3K-specific inhibitor BKM-120. Integrated RNA sequencing and high-throughput drug screening revealed that the Aurora A kinase (Aurora A)/Polo-like kinase 1 (PLK1)/cyclin-dependent kinase 1 (CDK1) signaling pathway was the main driver of PI3K inhibitor resistance in the resistant xenografts. Aurora kinase was upregulated and pCDK1 was downregulated in resistant tumors from both xenografts and tumor tissues from patients treated with the PI3K inhibitor. Mechanistically, the tyrosine kinase receptor Tie2 physically interacted with FGFR1, promoting STAT3 phosphorylation and binding to the
promoter, which increased Aurora A expression in resistant GSCs. Concurrent inhibition of Aurora A and PI3K signaling overcame PI3K inhibitor-induced resistance. This study offers a proof of concept to target PI3K and the collateral-activated pathway to improve GBM therapy. SIGNIFICANCE: These findings provide novel insights into the mechanisms of PI3K inhibitor resistance in glioblastoma.</description><subject>Animals</subject><subject>Aurora Kinase A - metabolism</subject><subject>CDC2 Protein Kinase - metabolism</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Drug Resistance, Neoplasm - physiology</subject><subject>Glioblastoma - pathology</subject><subject>Heterografts</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Polo-Like Kinase 1</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Receptor, Fibroblast Growth Factor, Type 1 - metabolism</subject><subject>Receptor, TIE-2 - metabolism</subject><subject>Signal Transduction - physiology</subject><subject>Up-Regulation</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kE2P0zAQhi0EYrsLPwHkI5dsPf6Kc4zKtlStYLXsni03nhSjNCm2g7QXfjuJ9uM078y874z0EPIJ2DWAMkvGmCmULPn1qv5eQFUwwdUbsgAlTFFKqd6Sxavnglym9HtqFTD1nlwIkKCN1Avy7z4gL9ab9R3QbZ8xuiaHoZ-0HxtMtPbunMNfpLdbsZumv8Ih5CHSO0whZdc3SA-P9OEc8Th2Lof-SOsxDtHRenm738Fy9XUH9Gc49q6bl6Gnmy4Mh86lPJzcB_KudV3Cj8_1ijysb-5X34r9j812Ve-LRiidC9BMK_TKeSc1a51UjgkAAZVWvPQOvfHeoPSMCe31pHlbARrmW8lNacQV-fJ09xyHPyOmbE8hNdh1rsdhTJbzUvHKVGU5WdWTtYlDShFbe47h5OKjBWZn9HbGamesdkJvobIz-in3-fnFeDihf029sBb_Adehfgg</recordid><startdate>20191001</startdate><enddate>20191001</enddate><creator>Li, Xiaolong</creator><creator>Martinez-Ledesma, Emmanuel</creator><creator>Zhang, Chen</creator><creator>Gao, Feng</creator><creator>Zheng, Siyuan</creator><creator>Ding, Jie</creator><creator>Wu, Shaofang</creator><creator>Nguyen, Nghi</creator><creator>Clifford, Stephan C</creator><creator>Wen, Patrick Y</creator><creator>Ligon, Keith L</creator><creator>Yung, W K Alfred</creator><creator>Koul, Dimpy</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><orcidid>https://orcid.org/0000-0002-1031-9424</orcidid></search><sort><creationdate>20191001</creationdate><title>Tie2-FGFR1 Interaction Induces Adaptive PI3K Inhibitor Resistance by Upregulating Aurora A/PLK1/CDK1 Signaling in Glioblastoma</title><author>Li, Xiaolong ; Martinez-Ledesma, Emmanuel ; Zhang, Chen ; Gao, Feng ; Zheng, Siyuan ; Ding, Jie ; Wu, Shaofang ; Nguyen, Nghi ; Clifford, Stephan C ; Wen, Patrick Y ; Ligon, Keith L ; Yung, W K Alfred ; Koul, Dimpy</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-16065ed5ada460fa45a03113196527daed8dd8e4d0036d6dd82f91e80df428783</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Aurora Kinase A - metabolism</topic><topic>CDC2 Protein Kinase - metabolism</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Drug Resistance, Neoplasm - physiology</topic><topic>Glioblastoma - pathology</topic><topic>Heterografts</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Polo-Like Kinase 1</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Serine-Threonine Kinases - metabolism</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Receptor, Fibroblast Growth Factor, Type 1 - metabolism</topic><topic>Receptor, TIE-2 - metabolism</topic><topic>Signal Transduction - physiology</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Xiaolong</creatorcontrib><creatorcontrib>Martinez-Ledesma, Emmanuel</creatorcontrib><creatorcontrib>Zhang, Chen</creatorcontrib><creatorcontrib>Gao, Feng</creatorcontrib><creatorcontrib>Zheng, Siyuan</creatorcontrib><creatorcontrib>Ding, Jie</creatorcontrib><creatorcontrib>Wu, Shaofang</creatorcontrib><creatorcontrib>Nguyen, Nghi</creatorcontrib><creatorcontrib>Clifford, Stephan C</creatorcontrib><creatorcontrib>Wen, Patrick Y</creatorcontrib><creatorcontrib>Ligon, Keith L</creatorcontrib><creatorcontrib>Yung, W K Alfred</creatorcontrib><creatorcontrib>Koul, Dimpy</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 research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Xiaolong</au><au>Martinez-Ledesma, Emmanuel</au><au>Zhang, Chen</au><au>Gao, Feng</au><au>Zheng, Siyuan</au><au>Ding, Jie</au><au>Wu, Shaofang</au><au>Nguyen, Nghi</au><au>Clifford, Stephan C</au><au>Wen, Patrick Y</au><au>Ligon, Keith L</au><au>Yung, W K Alfred</au><au>Koul, Dimpy</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tie2-FGFR1 Interaction Induces Adaptive PI3K Inhibitor Resistance by Upregulating Aurora A/PLK1/CDK1 Signaling in Glioblastoma</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2019-10-01</date><risdate>2019</risdate><volume>79</volume><issue>19</issue><spage>5088</spage><epage>5101</epage><pages>5088-5101</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><abstract>PI3K-targeting therapy represents one of the most sought-after therapies for glioblastoma (GBM). Several small-molecule inhibitors have been evaluated in clinical trials, however, the emergence of resistance limits treatment potential. Here, we generated a patient-derived glioma sphere-forming cell (GSC) xenograft model resistant to the PI3K-specific inhibitor BKM-120. Integrated RNA sequencing and high-throughput drug screening revealed that the Aurora A kinase (Aurora A)/Polo-like kinase 1 (PLK1)/cyclin-dependent kinase 1 (CDK1) signaling pathway was the main driver of PI3K inhibitor resistance in the resistant xenografts. Aurora kinase was upregulated and pCDK1 was downregulated in resistant tumors from both xenografts and tumor tissues from patients treated with the PI3K inhibitor. Mechanistically, the tyrosine kinase receptor Tie2 physically interacted with FGFR1, promoting STAT3 phosphorylation and binding to the
promoter, which increased Aurora A expression in resistant GSCs. Concurrent inhibition of Aurora A and PI3K signaling overcame PI3K inhibitor-induced resistance. This study offers a proof of concept to target PI3K and the collateral-activated pathway to improve GBM therapy. SIGNIFICANCE: These findings provide novel insights into the mechanisms of PI3K inhibitor resistance in glioblastoma.</abstract><cop>United States</cop><pmid>31416846</pmid><doi>10.1158/0008-5472.CAN-19-0325</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-1031-9424</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer research (Chicago, Ill.), 2019-10, Vol.79 (19), p.5088-5101 |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Aurora Kinase A - metabolism CDC2 Protein Kinase - metabolism Cell Cycle Proteins - metabolism Drug Resistance, Neoplasm - physiology Glioblastoma - pathology Heterografts Humans Male Mice Mice, Nude Phosphatidylinositol 3-Kinases - metabolism Polo-Like Kinase 1 Protein Kinase Inhibitors - pharmacology Protein Serine-Threonine Kinases - metabolism Proto-Oncogene Proteins - metabolism Receptor, Fibroblast Growth Factor, Type 1 - metabolism Receptor, TIE-2 - metabolism Signal Transduction - physiology Up-Regulation |
| title | Tie2-FGFR1 Interaction Induces Adaptive PI3K Inhibitor Resistance by Upregulating Aurora A/PLK1/CDK1 Signaling in Glioblastoma |
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