Isoform-Specific Phosphoinositide 3-Kinase Inhibitors Exert Distinct Effects in Solid Tumors
Therapeutic inhibitors are being developed against the phosphoinositide 3-kinase (PI3K) pathway, the deregulation of which drives tumor growth and survival in many cancers. There are eight PI3Ks in mammals divided into three classes. Class IA PI3Ks (p110alpha, p110beta, and p110delta) are critical f...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2010-02, Vol.70 (3), p.1164-1172 |
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| creator | EDGAR, Kyle A WALLIN, Jeffrey J BERRY, Megan LEE, Leslie B PRIOR, Wei Wei SAMPATH, Deepak FRIEDMAN, Lori S BELVIN, Marcia |
| description | Therapeutic inhibitors are being developed against the phosphoinositide 3-kinase (PI3K) pathway, the deregulation of which drives tumor growth and survival in many cancers. There are eight PI3Ks in mammals divided into three classes. Class IA PI3Ks (p110alpha, p110beta, and p110delta) are critical for cell growth and survival, with the p110alpha isoform implicated as the most important in carcinomas. In this study, we examined the effects of small-molecule inhibitors of class IA PI3Ks to explore the contributions of different isoforms in cancer cells. Similar responses were seen in cancer cells with wild-type or activated mutant PI3K genes treated with p110alpha/delta or p110alpha/beta/delta inhibitors in cell viability assays. In contrast, PTEN-negative cell lines tended to be less responsive (4-fold overall) to an inhibitor of p110alpha/delta versus p110alpha/beta/delta. Combining a p110alpha/delta inhibitor with a p110beta inhibitor resulted in comparable potency to the p110alpha/beta/delta inhibitor. The disparity in efficacy was confirmed in vivo. Pharmacodynamic biomarker analysis revealed that an inhibitor with insufficient potency against the p110beta isoform was less effective at inhibiting the PI3K pathway in PTEN-negative tumor xenografts. Our results imply that patients with PTEN-negative tumors may preferentially benefit from treatment with a class I PI3K inhibitor that is capable of inhibiting the p110beta isoform. |
| doi_str_mv | 10.1158/0008-5472.CAN-09-2525 |
| format | Article |
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There are eight PI3Ks in mammals divided into three classes. Class IA PI3Ks (p110alpha, p110beta, and p110delta) are critical for cell growth and survival, with the p110alpha isoform implicated as the most important in carcinomas. In this study, we examined the effects of small-molecule inhibitors of class IA PI3Ks to explore the contributions of different isoforms in cancer cells. Similar responses were seen in cancer cells with wild-type or activated mutant PI3K genes treated with p110alpha/delta or p110alpha/beta/delta inhibitors in cell viability assays. In contrast, PTEN-negative cell lines tended to be less responsive (4-fold overall) to an inhibitor of p110alpha/delta versus p110alpha/beta/delta. Combining a p110alpha/delta inhibitor with a p110beta inhibitor resulted in comparable potency to the p110alpha/beta/delta inhibitor. The disparity in efficacy was confirmed in vivo. Pharmacodynamic biomarker analysis revealed that an inhibitor with insufficient potency against the p110beta isoform was less effective at inhibiting the PI3K pathway in PTEN-negative tumor xenografts. Our results imply that patients with PTEN-negative tumors may preferentially benefit from treatment with a class I PI3K inhibitor that is capable of inhibiting the p110beta isoform.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-09-2525</identifier><identifier>PMID: 20103642</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic agents ; Biological and medical sciences ; Blotting, Western ; Cell Cycle - drug effects ; Cell Line, Tumor ; Cell Survival - drug effects ; Dose-Response Relationship, Drug ; Female ; Flow Cytometry ; Humans ; Indazoles - chemistry ; Indazoles - pharmacology ; Isoenzymes - antagonists & inhibitors ; Isoenzymes - metabolism ; Male ; Medical sciences ; Mice ; Mice, Nude ; Molecular Structure ; Multiple tumors. Solid tumors. Tumors in childhood (general aspects) ; Mutation ; Oncogene Protein v-akt - metabolism ; Pharmacology. Drug treatments ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphatidylinositol 3-Kinases - genetics ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphorylation ; Prostatic Neoplasms - drug therapy ; Prostatic Neoplasms - metabolism ; Prostatic Neoplasms - pathology ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; PTEN Phosphohydrolase - genetics ; PTEN Phosphohydrolase - metabolism ; Sulfonamides - chemistry ; Sulfonamides - pharmacology ; Tumors ; Xenograft Model Antitumor Assays</subject><ispartof>Cancer research (Chicago, Ill.), 2010-02, Vol.70 (3), p.1164-1172</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c418t-bca48dd85d86443f4a0fa718b815ad2010355305f5a93ecdb59021d25246caad3</citedby><cites>FETCH-LOGICAL-c418t-bca48dd85d86443f4a0fa718b815ad2010355305f5a93ecdb59021d25246caad3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3356,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22486743$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20103642$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>EDGAR, Kyle A</creatorcontrib><creatorcontrib>WALLIN, Jeffrey J</creatorcontrib><creatorcontrib>BERRY, Megan</creatorcontrib><creatorcontrib>LEE, Leslie B</creatorcontrib><creatorcontrib>PRIOR, Wei Wei</creatorcontrib><creatorcontrib>SAMPATH, Deepak</creatorcontrib><creatorcontrib>FRIEDMAN, Lori S</creatorcontrib><creatorcontrib>BELVIN, Marcia</creatorcontrib><title>Isoform-Specific Phosphoinositide 3-Kinase Inhibitors Exert Distinct Effects in Solid Tumors</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Therapeutic inhibitors are being developed against the phosphoinositide 3-kinase (PI3K) pathway, the deregulation of which drives tumor growth and survival in many cancers. There are eight PI3Ks in mammals divided into three classes. Class IA PI3Ks (p110alpha, p110beta, and p110delta) are critical for cell growth and survival, with the p110alpha isoform implicated as the most important in carcinomas. In this study, we examined the effects of small-molecule inhibitors of class IA PI3Ks to explore the contributions of different isoforms in cancer cells. Similar responses were seen in cancer cells with wild-type or activated mutant PI3K genes treated with p110alpha/delta or p110alpha/beta/delta inhibitors in cell viability assays. In contrast, PTEN-negative cell lines tended to be less responsive (4-fold overall) to an inhibitor of p110alpha/delta versus p110alpha/beta/delta. Combining a p110alpha/delta inhibitor with a p110beta inhibitor resulted in comparable potency to the p110alpha/beta/delta inhibitor. The disparity in efficacy was confirmed in vivo. Pharmacodynamic biomarker analysis revealed that an inhibitor with insufficient potency against the p110beta isoform was less effective at inhibiting the PI3K pathway in PTEN-negative tumor xenografts. Our results imply that patients with PTEN-negative tumors may preferentially benefit from treatment with a class I PI3K inhibitor that is capable of inhibiting the p110beta isoform.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Female</subject><subject>Flow Cytometry</subject><subject>Humans</subject><subject>Indazoles - chemistry</subject><subject>Indazoles - pharmacology</subject><subject>Isoenzymes - antagonists & inhibitors</subject><subject>Isoenzymes - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Molecular Structure</subject><subject>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</subject><subject>Mutation</subject><subject>Oncogene Protein v-akt - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphorylation</subject><subject>Prostatic Neoplasms - drug therapy</subject><subject>Prostatic Neoplasms - metabolism</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>PTEN Phosphohydrolase - genetics</subject><subject>PTEN Phosphohydrolase - metabolism</subject><subject>Sulfonamides - chemistry</subject><subject>Sulfonamides - pharmacology</subject><subject>Tumors</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkE1PGzEQhi1EBSn0J4B8QZwM9tqz6xxRGtqoqEUCbpUsrz8Uo9118Gyk8u-7gZSeRiM973w8hJwJfiUE6GvOuWagmupqcfOT8TmroIIDMhMgNWuUgkMy-2COyWfE56kFweGIHFdccFmrakZ-rzDHXHr2sAkuxeTo_TrjZp3TkDGNyQcq2Y80WAx0NaxTm8ZckC7_hDLSrwnHNLiRLmMMbkSaBvqQu-Tp47afsFPyKdoOw5d9PSFPt8vHxXd29-vbanFzx5wSemSts0p7r8HrWikZleXRNkK3WoD1b7cCSA4R7FwG51uY80r46WFVO2u9PCGX73M3Jb9sA46mT-hC19kh5C2aRspaywaaiYR30pWMWEI0m5J6W16N4Gbn1eycmZ0zM3k1fG52Xqfc-X7Dtu2D_0j9EzkBF3vAorNdLHZwCf9zldJ1o6T8C9PvgJQ</recordid><startdate>20100201</startdate><enddate>20100201</enddate><creator>EDGAR, Kyle A</creator><creator>WALLIN, Jeffrey J</creator><creator>BERRY, Megan</creator><creator>LEE, Leslie B</creator><creator>PRIOR, Wei Wei</creator><creator>SAMPATH, Deepak</creator><creator>FRIEDMAN, Lori S</creator><creator>BELVIN, Marcia</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><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>20100201</creationdate><title>Isoform-Specific Phosphoinositide 3-Kinase Inhibitors Exert Distinct Effects in Solid Tumors</title><author>EDGAR, Kyle A ; WALLIN, Jeffrey J ; BERRY, Megan ; LEE, Leslie B ; PRIOR, Wei Wei ; SAMPATH, Deepak ; FRIEDMAN, Lori S ; BELVIN, Marcia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c418t-bca48dd85d86443f4a0fa718b815ad2010355305f5a93ecdb59021d25246caad3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>Cell Cycle - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Female</topic><topic>Flow Cytometry</topic><topic>Humans</topic><topic>Indazoles - chemistry</topic><topic>Indazoles - pharmacology</topic><topic>Isoenzymes - antagonists & inhibitors</topic><topic>Isoenzymes - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Molecular Structure</topic><topic>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</topic><topic>Mutation</topic><topic>Oncogene Protein v-akt - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>Phosphatidylinositol 3-Kinases - genetics</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphorylation</topic><topic>Prostatic Neoplasms - drug therapy</topic><topic>Prostatic Neoplasms - metabolism</topic><topic>Prostatic Neoplasms - pathology</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>PTEN Phosphohydrolase - genetics</topic><topic>PTEN Phosphohydrolase - metabolism</topic><topic>Sulfonamides - chemistry</topic><topic>Sulfonamides - pharmacology</topic><topic>Tumors</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>EDGAR, Kyle A</creatorcontrib><creatorcontrib>WALLIN, Jeffrey J</creatorcontrib><creatorcontrib>BERRY, Megan</creatorcontrib><creatorcontrib>LEE, Leslie B</creatorcontrib><creatorcontrib>PRIOR, Wei Wei</creatorcontrib><creatorcontrib>SAMPATH, Deepak</creatorcontrib><creatorcontrib>FRIEDMAN, Lori S</creatorcontrib><creatorcontrib>BELVIN, Marcia</creatorcontrib><collection>Pascal-Francis</collection><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>EDGAR, Kyle A</au><au>WALLIN, Jeffrey J</au><au>BERRY, Megan</au><au>LEE, Leslie B</au><au>PRIOR, Wei Wei</au><au>SAMPATH, Deepak</au><au>FRIEDMAN, Lori S</au><au>BELVIN, Marcia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Isoform-Specific Phosphoinositide 3-Kinase Inhibitors Exert Distinct Effects in Solid Tumors</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2010-02-01</date><risdate>2010</risdate><volume>70</volume><issue>3</issue><spage>1164</spage><epage>1172</epage><pages>1164-1172</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>Therapeutic inhibitors are being developed against the phosphoinositide 3-kinase (PI3K) pathway, the deregulation of which drives tumor growth and survival in many cancers. There are eight PI3Ks in mammals divided into three classes. Class IA PI3Ks (p110alpha, p110beta, and p110delta) are critical for cell growth and survival, with the p110alpha isoform implicated as the most important in carcinomas. In this study, we examined the effects of small-molecule inhibitors of class IA PI3Ks to explore the contributions of different isoforms in cancer cells. Similar responses were seen in cancer cells with wild-type or activated mutant PI3K genes treated with p110alpha/delta or p110alpha/beta/delta inhibitors in cell viability assays. In contrast, PTEN-negative cell lines tended to be less responsive (4-fold overall) to an inhibitor of p110alpha/delta versus p110alpha/beta/delta. Combining a p110alpha/delta inhibitor with a p110beta inhibitor resulted in comparable potency to the p110alpha/beta/delta inhibitor. The disparity in efficacy was confirmed in vivo. Pharmacodynamic biomarker analysis revealed that an inhibitor with insufficient potency against the p110beta isoform was less effective at inhibiting the PI3K pathway in PTEN-negative tumor xenografts. Our results imply that patients with PTEN-negative tumors may preferentially benefit from treatment with a class I PI3K inhibitor that is capable of inhibiting the p110beta isoform.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>20103642</pmid><doi>10.1158/0008-5472.CAN-09-2525</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer research (Chicago, Ill.), 2010-02, Vol.70 (3), p.1164-1172 |
| issn | 0008-5472 1538-7445 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research |
| subjects | Animals Antineoplastic agents Biological and medical sciences Blotting, Western Cell Cycle - drug effects Cell Line, Tumor Cell Survival - drug effects Dose-Response Relationship, Drug Female Flow Cytometry Humans Indazoles - chemistry Indazoles - pharmacology Isoenzymes - antagonists & inhibitors Isoenzymes - metabolism Male Medical sciences Mice Mice, Nude Molecular Structure Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Mutation Oncogene Protein v-akt - metabolism Pharmacology. Drug treatments Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - metabolism Phosphorylation Prostatic Neoplasms - drug therapy Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology PTEN Phosphohydrolase - genetics PTEN Phosphohydrolase - metabolism Sulfonamides - chemistry Sulfonamides - pharmacology Tumors Xenograft Model Antitumor Assays |
| title | Isoform-Specific Phosphoinositide 3-Kinase Inhibitors Exert Distinct Effects in Solid Tumors |
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