Evaluation of Tumor Cell-Tumor Microenvironment Component Interactions as Potential Predictors of Patient Response to Napabucasin
Napabucasin is an NAD(P)H:quinone oxidoreductase 1 (NQO1)-bioactivatable small molecule hypothesized to affect multiple oncogenic pathways. In a prespecified, retrospective analysis of the napabucasin phase III CO.23 study, overall survival was longer for napabucasin versus placebo in patients expre...
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| Veröffentlicht in: | Molecular cancer research 2019-07, Vol.17 (7), p.1429-1434 |
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| creator | Chang, An-Yun Hsu, Eric Patel, Jaimin Li, Yiqun Zhang, Minjie Iguchi, Haruhisa Rogoff, Harry A |
| description | Napabucasin is an NAD(P)H:quinone oxidoreductase 1 (NQO1)-bioactivatable small molecule hypothesized to affect multiple oncogenic pathways. In a prespecified, retrospective analysis of the napabucasin phase III CO.23 study, overall survival was longer for napabucasin versus placebo in patients expressing phosphorylated STAT3 (pSTAT3) in tumor cells and cells of the tumor microenvironment (TME). We hypothesized that a connection may exist between NQO1 expression in cancer cells and pSTAT3 in tumor cells and the TME. In 3D spheroid cocultures of cancer cells and cancer-associated fibroblasts, the antitumor activity of napabucasin was NQO1 dependent. The levels of cytokines such as IL6, CXCL10, and GM-CSF were higher in NQO1-positive versus NQO1-deleted cocultures. These differentially secreted cytokines promoted STAT3 phosphorylation in tumor cells and the TME. NQO1-expressing, napabucasin-sensitive tumor cells can modify tumor cells and the TME to promote STAT3 phosphorylation, suggesting that pSTAT3 may be used to identify a subpopulation of patients who would likely respond to napabucasin. IMPLICATIONS: pSTAT3 is a potential biomarker for patient response to the anticancer drug napabucasin.
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| doi_str_mv | 10.1158/1541-7786.MCR-18-1242 |
| format | Article |
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http://mcr.aacrjournals.org/content/molcanres/17/7/1429/F1.large.jpg.</description><subject>Benzofurans - pharmacology</subject><subject>Cancer-Associated Fibroblasts - drug effects</subject><subject>Carcinogenesis - drug effects</subject><subject>Carcinoma, Squamous Cell - drug therapy</subject><subject>Carcinoma, Squamous Cell - genetics</subject><subject>Carcinoma, Squamous Cell - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Lineage - drug effects</subject><subject>Coculture Techniques</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Humans</subject><subject>Hypopharyngeal Neoplasms - drug therapy</subject><subject>Hypopharyngeal Neoplasms - genetics</subject><subject>Hypopharyngeal Neoplasms - pathology</subject><subject>NAD(P)H Dehydrogenase (Quinone) - genetics</subject><subject>Naphthoquinones - pharmacology</subject><subject>STAT3 Transcription Factor - genetics</subject><subject>Tumor Microenvironment - drug effects</subject><issn>1541-7786</issn><issn>1557-3125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kFFLwzAUhYMoTqc_QcmjL525Sdqkj1KmDjYdYz6HtE2h0jY1aQc--s9N2fTpHi7nnMv9ELoDsgCI5SPEHCIhZLLYZLsIZASU0zN0BXEsIgY0Pp_0yTND195_EkIJiOQSzRgQznhKrtDP8qCbUQ-17bCt8H5srcOZaZroKDd14azpDrWzXWu6AWe27W03qVU3GKeLKeqx9nhrh7CudYO3zpR1MVjnp85taJ_8O-ND0hs8WPyme52PhfZ1d4MuKt14c3uac_TxvNxnr9H6_WWVPa2jglM6RCIWQoM0ZQ6VFCllhmsJshK5pFVa5oIbLahgPCloZeI0BwGsIIJRkCRlOZujh2Nv7-zXaPyg2toX4VPdGTt6RYMxTVOeQLDGR2v43XtnKtW7utXuWwFRE301kVUTWRXoKwiLQD_k7k8nxrw15X_qDzf7BeGDgm8</recordid><startdate>201907</startdate><enddate>201907</enddate><creator>Chang, An-Yun</creator><creator>Hsu, Eric</creator><creator>Patel, Jaimin</creator><creator>Li, Yiqun</creator><creator>Zhang, Minjie</creator><creator>Iguchi, Haruhisa</creator><creator>Rogoff, Harry A</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>201907</creationdate><title>Evaluation of Tumor Cell-Tumor Microenvironment Component Interactions as Potential Predictors of Patient Response to Napabucasin</title><author>Chang, An-Yun ; Hsu, Eric ; Patel, Jaimin ; Li, Yiqun ; Zhang, Minjie ; Iguchi, Haruhisa ; Rogoff, Harry A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c422t-7577a18edb1f87923e4a818f7b82f9db74ea727346c2fe59b1713c073218093b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Benzofurans - pharmacology</topic><topic>Cancer-Associated Fibroblasts - drug effects</topic><topic>Carcinogenesis - drug effects</topic><topic>Carcinoma, Squamous Cell - drug therapy</topic><topic>Carcinoma, Squamous Cell - genetics</topic><topic>Carcinoma, Squamous Cell - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Lineage - drug effects</topic><topic>Coculture Techniques</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Humans</topic><topic>Hypopharyngeal Neoplasms - drug therapy</topic><topic>Hypopharyngeal Neoplasms - genetics</topic><topic>Hypopharyngeal Neoplasms - pathology</topic><topic>NAD(P)H Dehydrogenase (Quinone) - genetics</topic><topic>Naphthoquinones - pharmacology</topic><topic>STAT3 Transcription Factor - genetics</topic><topic>Tumor Microenvironment - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chang, An-Yun</creatorcontrib><creatorcontrib>Hsu, Eric</creatorcontrib><creatorcontrib>Patel, Jaimin</creatorcontrib><creatorcontrib>Li, Yiqun</creatorcontrib><creatorcontrib>Zhang, Minjie</creatorcontrib><creatorcontrib>Iguchi, Haruhisa</creatorcontrib><creatorcontrib>Rogoff, Harry A</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>Molecular cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chang, An-Yun</au><au>Hsu, Eric</au><au>Patel, Jaimin</au><au>Li, Yiqun</au><au>Zhang, Minjie</au><au>Iguchi, Haruhisa</au><au>Rogoff, Harry A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evaluation of Tumor Cell-Tumor Microenvironment Component Interactions as Potential Predictors of Patient Response to Napabucasin</atitle><jtitle>Molecular cancer research</jtitle><addtitle>Mol Cancer Res</addtitle><date>2019-07</date><risdate>2019</risdate><volume>17</volume><issue>7</issue><spage>1429</spage><epage>1434</epage><pages>1429-1434</pages><issn>1541-7786</issn><eissn>1557-3125</eissn><abstract>Napabucasin is an NAD(P)H:quinone oxidoreductase 1 (NQO1)-bioactivatable small molecule hypothesized to affect multiple oncogenic pathways. In a prespecified, retrospective analysis of the napabucasin phase III CO.23 study, overall survival was longer for napabucasin versus placebo in patients expressing phosphorylated STAT3 (pSTAT3) in tumor cells and cells of the tumor microenvironment (TME). We hypothesized that a connection may exist between NQO1 expression in cancer cells and pSTAT3 in tumor cells and the TME. In 3D spheroid cocultures of cancer cells and cancer-associated fibroblasts, the antitumor activity of napabucasin was NQO1 dependent. The levels of cytokines such as IL6, CXCL10, and GM-CSF were higher in NQO1-positive versus NQO1-deleted cocultures. These differentially secreted cytokines promoted STAT3 phosphorylation in tumor cells and the TME. NQO1-expressing, napabucasin-sensitive tumor cells can modify tumor cells and the TME to promote STAT3 phosphorylation, suggesting that pSTAT3 may be used to identify a subpopulation of patients who would likely respond to napabucasin. IMPLICATIONS: pSTAT3 is a potential biomarker for patient response to the anticancer drug napabucasin.
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| subjects | Benzofurans - pharmacology Cancer-Associated Fibroblasts - drug effects Carcinogenesis - drug effects Carcinoma, Squamous Cell - drug therapy Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - pathology Cell Line, Tumor Cell Lineage - drug effects Coculture Techniques Gene Expression Regulation, Neoplastic - drug effects Humans Hypopharyngeal Neoplasms - drug therapy Hypopharyngeal Neoplasms - genetics Hypopharyngeal Neoplasms - pathology NAD(P)H Dehydrogenase (Quinone) - genetics Naphthoquinones - pharmacology STAT3 Transcription Factor - genetics Tumor Microenvironment - drug effects |
| title | Evaluation of Tumor Cell-Tumor Microenvironment Component Interactions as Potential Predictors of Patient Response to Napabucasin |
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