Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer
Recent preclinical studies revealed the efficacy of combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib in breast and prostate cancers. The current study investigated the effect of such drug combination on ovarian cancer. Here we showed that combined inhibition of PI3K and PARP effecti...
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| Veröffentlicht in: | Oncotarget 2016-03, Vol.7 (11), p.13153-13166 |
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| creator | Wang, Dong Wang, Min Jiang, Nan Zhang, Yuan Bian, Xing Wang, Xiaoqing Roberts, Thomas M Zhao, Jean J Liu, Pixu Cheng, Hailing |
| description | Recent preclinical studies revealed the efficacy of combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib in breast and prostate cancers. The current study investigated the effect of such drug combination on ovarian cancer. Here we showed that combined inhibition of PI3K and PARP effectively synergized to inhibit proliferation, survival and invasion in the majority of ovarian cancer cell lines harboring PIK3CA mutations, including SKOV3, HEYA8, and IGROV1. Mechanistically, combined treatment of PARP and PI3K inhibitors resulted in an exacerbated DNA damage response and more substantially reduced AKT/mTOR signaling when compared to single-agent. Notably, ovarian cancer cells responsive to the PI3K/PARP combination displayed decreased BRCA1/2 expression upon drug treatment. Furthermore, the effect of the drug combination was corroborated in an intraperitoneal dissemination xenograft mouse model in which SKOV3 ovarian cancer cells responded with significantly decreased BRCA1 expression, suppressed PI3K/AKT signaling and reduced tumor burden. Collectively, our data suggested that combined inhibition of PI3K and PARP may be an effective therapeutic strategy for ovarian cancers with PIK3CA mutations and that the accompanied BRCA downregulation following PI3K inhibition could serve as a biomarker for the effective response to PARP inhibition. |
| doi_str_mv | 10.18632/oncotarget.7549 |
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| fullrecord | <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4914348</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>26909613</sourcerecordid><originalsourceid>FETCH-LOGICAL-c420t-13c7c74721f8fd99bf50f18b1b555ac1301d13b843e8f9ee8a8232b805ec8b653</originalsourceid><addsrcrecordid>eNpVkM1OAjEURhujEYLsXZm-wGB_Z9qNCRJUAgZidD1pOy3UwJR0Colv7yiKeDf3Jl_Od5MDwDVGAyxySm5DbUJScWnToOBMnoEulkxmhHN6fnJ3QL9p3lE7nBWCyEvQIblEMse0C1Zj56xJfm_hrrEwOLiY0Cn09cprn0KE99NnTBBUdQUXw5fFSTJfq62KXsMUYIpWpRad0tEQbnZJ1QmGfZuqGhpVGxuvwIVT68b2f3YPvD2MX0dP2Wz-OBkNZ5lhBKUMU1OYghUEO-EqKbXjyGGhseacK4MpwhWmWjBqhZPWCiUIJVogbo3QOac9cHfo3e70xlbG1imqdbmNfqPiRxmUL_8ntV-Vy7AvmcSMMtEWoEOBiaFponVHFqPyW3z5J778Et8iN6c_j8CvZvoJ5T-BlA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer</title><source>MEDLINE</source><source>Open Access: Freely Accessible Journals by multiple vendors</source><source>PubMed Central</source><source>EZB Electronic Journals Library</source><source>PubMed Central Open Access</source><creator>Wang, Dong ; Wang, Min ; Jiang, Nan ; Zhang, Yuan ; Bian, Xing ; Wang, Xiaoqing ; Roberts, Thomas M ; Zhao, Jean J ; Liu, Pixu ; Cheng, Hailing</creator><creatorcontrib>Wang, Dong ; Wang, Min ; Jiang, Nan ; Zhang, Yuan ; Bian, Xing ; Wang, Xiaoqing ; Roberts, Thomas M ; Zhao, Jean J ; Liu, Pixu ; Cheng, Hailing</creatorcontrib><description>Recent preclinical studies revealed the efficacy of combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib in breast and prostate cancers. The current study investigated the effect of such drug combination on ovarian cancer. Here we showed that combined inhibition of PI3K and PARP effectively synergized to inhibit proliferation, survival and invasion in the majority of ovarian cancer cell lines harboring PIK3CA mutations, including SKOV3, HEYA8, and IGROV1. Mechanistically, combined treatment of PARP and PI3K inhibitors resulted in an exacerbated DNA damage response and more substantially reduced AKT/mTOR signaling when compared to single-agent. Notably, ovarian cancer cells responsive to the PI3K/PARP combination displayed decreased BRCA1/2 expression upon drug treatment. Furthermore, the effect of the drug combination was corroborated in an intraperitoneal dissemination xenograft mouse model in which SKOV3 ovarian cancer cells responded with significantly decreased BRCA1 expression, suppressed PI3K/AKT signaling and reduced tumor burden. Collectively, our data suggested that combined inhibition of PI3K and PARP may be an effective therapeutic strategy for ovarian cancers with PIK3CA mutations and that the accompanied BRCA downregulation following PI3K inhibition could serve as a biomarker for the effective response to PARP inhibition.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.7549</identifier><identifier>PMID: 26909613</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Aminopyridines - pharmacology ; Animals ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Class I Phosphatidylinositol 3-Kinases - genetics ; Drug Synergism ; Female ; Humans ; Mice ; Morpholines - pharmacology ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - genetics ; Phthalazines - pharmacology ; Piperazines - pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology ; Research Paper ; Xenograft Model Antitumor Assays</subject><ispartof>Oncotarget, 2016-03, Vol.7 (11), p.13153-13166</ispartof><rights>Copyright: © 2016 Wang et al. 2016</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c420t-13c7c74721f8fd99bf50f18b1b555ac1301d13b843e8f9ee8a8232b805ec8b653</citedby><cites>FETCH-LOGICAL-c420t-13c7c74721f8fd99bf50f18b1b555ac1301d13b843e8f9ee8a8232b805ec8b653</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/PMC4914348/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914348/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26909613$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Dong</creatorcontrib><creatorcontrib>Wang, Min</creatorcontrib><creatorcontrib>Jiang, Nan</creatorcontrib><creatorcontrib>Zhang, Yuan</creatorcontrib><creatorcontrib>Bian, Xing</creatorcontrib><creatorcontrib>Wang, Xiaoqing</creatorcontrib><creatorcontrib>Roberts, Thomas M</creatorcontrib><creatorcontrib>Zhao, Jean J</creatorcontrib><creatorcontrib>Liu, Pixu</creatorcontrib><creatorcontrib>Cheng, Hailing</creatorcontrib><title>Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>Recent preclinical studies revealed the efficacy of combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib in breast and prostate cancers. The current study investigated the effect of such drug combination on ovarian cancer. Here we showed that combined inhibition of PI3K and PARP effectively synergized to inhibit proliferation, survival and invasion in the majority of ovarian cancer cell lines harboring PIK3CA mutations, including SKOV3, HEYA8, and IGROV1. Mechanistically, combined treatment of PARP and PI3K inhibitors resulted in an exacerbated DNA damage response and more substantially reduced AKT/mTOR signaling when compared to single-agent. Notably, ovarian cancer cells responsive to the PI3K/PARP combination displayed decreased BRCA1/2 expression upon drug treatment. Furthermore, the effect of the drug combination was corroborated in an intraperitoneal dissemination xenograft mouse model in which SKOV3 ovarian cancer cells responded with significantly decreased BRCA1 expression, suppressed PI3K/AKT signaling and reduced tumor burden. Collectively, our data suggested that combined inhibition of PI3K and PARP may be an effective therapeutic strategy for ovarian cancers with PIK3CA mutations and that the accompanied BRCA downregulation following PI3K inhibition could serve as a biomarker for the effective response to PARP inhibition.</description><subject>Aminopyridines - pharmacology</subject><subject>Animals</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Class I Phosphatidylinositol 3-Kinases - genetics</subject><subject>Drug Synergism</subject><subject>Female</subject><subject>Humans</subject><subject>Mice</subject><subject>Morpholines - pharmacology</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Phthalazines - pharmacology</subject><subject>Piperazines - pharmacology</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors - pharmacology</subject><subject>Research Paper</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkM1OAjEURhujEYLsXZm-wGB_Z9qNCRJUAgZidD1pOy3UwJR0Colv7yiKeDf3Jl_Od5MDwDVGAyxySm5DbUJScWnToOBMnoEulkxmhHN6fnJ3QL9p3lE7nBWCyEvQIblEMse0C1Zj56xJfm_hrrEwOLiY0Cn09cprn0KE99NnTBBUdQUXw5fFSTJfq62KXsMUYIpWpRad0tEQbnZJ1QmGfZuqGhpVGxuvwIVT68b2f3YPvD2MX0dP2Wz-OBkNZ5lhBKUMU1OYghUEO-EqKbXjyGGhseacK4MpwhWmWjBqhZPWCiUIJVogbo3QOac9cHfo3e70xlbG1imqdbmNfqPiRxmUL_8ntV-Vy7AvmcSMMtEWoEOBiaFponVHFqPyW3z5J778Et8iN6c_j8CvZvoJ5T-BlA</recordid><startdate>20160315</startdate><enddate>20160315</enddate><creator>Wang, Dong</creator><creator>Wang, Min</creator><creator>Jiang, Nan</creator><creator>Zhang, Yuan</creator><creator>Bian, Xing</creator><creator>Wang, Xiaoqing</creator><creator>Roberts, Thomas M</creator><creator>Zhao, Jean J</creator><creator>Liu, Pixu</creator><creator>Cheng, Hailing</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>5PM</scope></search><sort><creationdate>20160315</creationdate><title>Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer</title><author>Wang, Dong ; Wang, Min ; Jiang, Nan ; Zhang, Yuan ; Bian, Xing ; Wang, Xiaoqing ; Roberts, Thomas M ; Zhao, Jean J ; Liu, Pixu ; Cheng, Hailing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c420t-13c7c74721f8fd99bf50f18b1b555ac1301d13b843e8f9ee8a8232b805ec8b653</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Aminopyridines - pharmacology</topic><topic>Animals</topic><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>Class I Phosphatidylinositol 3-Kinases - genetics</topic><topic>Drug Synergism</topic><topic>Female</topic><topic>Humans</topic><topic>Mice</topic><topic>Morpholines - pharmacology</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - genetics</topic><topic>Phthalazines - pharmacology</topic><topic>Piperazines - pharmacology</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors - pharmacology</topic><topic>Research Paper</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>online_resources</toplevel><creatorcontrib>Wang, Dong</creatorcontrib><creatorcontrib>Wang, Min</creatorcontrib><creatorcontrib>Jiang, Nan</creatorcontrib><creatorcontrib>Zhang, Yuan</creatorcontrib><creatorcontrib>Bian, Xing</creatorcontrib><creatorcontrib>Wang, Xiaoqing</creatorcontrib><creatorcontrib>Roberts, Thomas M</creatorcontrib><creatorcontrib>Zhao, Jean J</creatorcontrib><creatorcontrib>Liu, Pixu</creatorcontrib><creatorcontrib>Cheng, Hailing</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Dong</au><au>Wang, Min</au><au>Jiang, Nan</au><au>Zhang, Yuan</au><au>Bian, Xing</au><au>Wang, Xiaoqing</au><au>Roberts, Thomas M</au><au>Zhao, Jean J</au><au>Liu, Pixu</au><au>Cheng, Hailing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2016-03-15</date><risdate>2016</risdate><volume>7</volume><issue>11</issue><spage>13153</spage><epage>13166</epage><pages>13153-13166</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>Recent preclinical studies revealed the efficacy of combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib in breast and prostate cancers. The current study investigated the effect of such drug combination on ovarian cancer. Here we showed that combined inhibition of PI3K and PARP effectively synergized to inhibit proliferation, survival and invasion in the majority of ovarian cancer cell lines harboring PIK3CA mutations, including SKOV3, HEYA8, and IGROV1. Mechanistically, combined treatment of PARP and PI3K inhibitors resulted in an exacerbated DNA damage response and more substantially reduced AKT/mTOR signaling when compared to single-agent. Notably, ovarian cancer cells responsive to the PI3K/PARP combination displayed decreased BRCA1/2 expression upon drug treatment. Furthermore, the effect of the drug combination was corroborated in an intraperitoneal dissemination xenograft mouse model in which SKOV3 ovarian cancer cells responded with significantly decreased BRCA1 expression, suppressed PI3K/AKT signaling and reduced tumor burden. Collectively, our data suggested that combined inhibition of PI3K and PARP may be an effective therapeutic strategy for ovarian cancers with PIK3CA mutations and that the accompanied BRCA downregulation following PI3K inhibition could serve as a biomarker for the effective response to PARP inhibition.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>26909613</pmid><doi>10.18632/oncotarget.7549</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aminopyridines - pharmacology Animals Antineoplastic Combined Chemotherapy Protocols - pharmacology Cell Line, Tumor Cell Proliferation - drug effects Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors Class I Phosphatidylinositol 3-Kinases - genetics Drug Synergism Female Humans Mice Morpholines - pharmacology Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Phthalazines - pharmacology Piperazines - pharmacology Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Research Paper Xenograft Model Antitumor Assays |
| title | Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer |
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