Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination
Fewer than half of children with high-risk neuroblastoma survive. Many of these tumors harbor high-level amplification of MYCN, which correlates with poor disease outcome. Using data from our large drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensit...
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| creator | Ham, Jungoh Costa, Carlotta Sano, Renata Lochmann, Timothy L. Sennott, Erin M. Patel, Neha U. Dastur, Anahita Gomez-Caraballo, Maria Krytska, Kateryna Hata, Aaron N. Floros, Konstantinos V. Hughes, Mark T. Jakubik, Charles T. Heisey, Daniel A.R. Ferrell, Justin T. Bristol, Molly L. March, Ryan J. Yates, Craig Hicks, Mark A. Nakajima, Wataru Gowda, Madhu Windle, Brad E. Dozmorov, Mikhail G. Garnett, Mathew J. McDermott, Ultan Harada, Hisashi Taylor, Shirley M. Morgan, Iain M. Benes, Cyril H. Engelman, Jeffrey A. Mossé, Yael P. Faber, Anthony C. |
| description | Fewer than half of children with high-risk neuroblastoma survive. Many of these tumors harbor high-level amplification of MYCN, which correlates with poor disease outcome. Using data from our large drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensitive to the BCL-2 inhibitor ABT-199. This sensitivity occurs in part through low anti-apoptotic BCL-xL expression, high pro-apoptotic NOXA expression, and paradoxical, MYCN-driven upregulation of NOXA. Screening for enhancers of ABT-199 sensitivity in MYCN-amplified neuroblastomas, we demonstrate that the Aurora Kinase A inhibitor MLN8237 combines with ABT-199 to induce widespread apoptosis. In diverse models of MYCN-amplified neuroblastoma, including a patient-derived xenograft model, this combination uniformly induced tumor shrinkage, and in multiple instances led to complete tumor regression.
[Display omitted]
•Amplified MYCN is synthetic lethal with the BCL-2 inhibitor ABT-199 in neuroblastoma•MYCN upregulates the MCL-1 inhibitor, NOXA•MYCN-amplified neuroblastomas are further sensitized to ABT-199 with MLN8237•ABT-199 with MLN8237 induce tumor regressions in MYCN-amplified neuroblastoma mice
Ham et al. show that MYCN-amplified neuroblastomas are sensitive to treatment with the BCL-2 inhibitor ABT-199 due to MYCN-driven increase of NOXA. Combination treatment with the Aurora Kinase A inhibitor MLN8237 and ABT-199 is synergistic in xenograft models of this tumor type, in part via reducing MCL-1. |
| doi_str_mv | 10.1016/j.ccell.2016.01.002 |
| format | Article |
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[Display omitted]
•Amplified MYCN is synthetic lethal with the BCL-2 inhibitor ABT-199 in neuroblastoma•MYCN upregulates the MCL-1 inhibitor, NOXA•MYCN-amplified neuroblastomas are further sensitized to ABT-199 with MLN8237•ABT-199 with MLN8237 induce tumor regressions in MYCN-amplified neuroblastoma mice
Ham et al. show that MYCN-amplified neuroblastomas are sensitive to treatment with the BCL-2 inhibitor ABT-199 due to MYCN-driven increase of NOXA. Combination treatment with the Aurora Kinase A inhibitor MLN8237 and ABT-199 is synergistic in xenograft models of this tumor type, in part via reducing MCL-1.</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/j.ccell.2016.01.002</identifier><identifier>PMID: 26859456</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Aniline Compounds - therapeutic use ; Antineoplastic Agents - therapeutic use ; Apoptosis - genetics ; Cell Line, Tumor ; Humans ; N-Myc Proto-Oncogene Protein ; Neuroblastoma - drug therapy ; Neuroblastoma - genetics ; Neuroblastoma - pathology ; Nuclear Proteins ; Oncogene Proteins ; Sulfonamides - therapeutic use</subject><ispartof>Cancer cell, 2016-02, Vol.29 (2), p.159-172</ispartof><rights>2016 The Authors</rights><rights>Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.</rights><rights>2016 The Authors 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c558t-d8eee7a2c97795da7f7b1b1ed19769736a169018c4efa488678621f41be6c7703</citedby><cites>FETCH-LOGICAL-c558t-d8eee7a2c97795da7f7b1b1ed19769736a169018c4efa488678621f41be6c7703</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1535610816000313$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26859456$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ham, Jungoh</creatorcontrib><creatorcontrib>Costa, Carlotta</creatorcontrib><creatorcontrib>Sano, Renata</creatorcontrib><creatorcontrib>Lochmann, Timothy L.</creatorcontrib><creatorcontrib>Sennott, Erin M.</creatorcontrib><creatorcontrib>Patel, Neha U.</creatorcontrib><creatorcontrib>Dastur, Anahita</creatorcontrib><creatorcontrib>Gomez-Caraballo, Maria</creatorcontrib><creatorcontrib>Krytska, Kateryna</creatorcontrib><creatorcontrib>Hata, Aaron N.</creatorcontrib><creatorcontrib>Floros, Konstantinos V.</creatorcontrib><creatorcontrib>Hughes, Mark T.</creatorcontrib><creatorcontrib>Jakubik, Charles T.</creatorcontrib><creatorcontrib>Heisey, Daniel A.R.</creatorcontrib><creatorcontrib>Ferrell, Justin T.</creatorcontrib><creatorcontrib>Bristol, Molly L.</creatorcontrib><creatorcontrib>March, Ryan J.</creatorcontrib><creatorcontrib>Yates, Craig</creatorcontrib><creatorcontrib>Hicks, Mark A.</creatorcontrib><creatorcontrib>Nakajima, Wataru</creatorcontrib><creatorcontrib>Gowda, Madhu</creatorcontrib><creatorcontrib>Windle, Brad E.</creatorcontrib><creatorcontrib>Dozmorov, Mikhail G.</creatorcontrib><creatorcontrib>Garnett, Mathew J.</creatorcontrib><creatorcontrib>McDermott, Ultan</creatorcontrib><creatorcontrib>Harada, Hisashi</creatorcontrib><creatorcontrib>Taylor, Shirley M.</creatorcontrib><creatorcontrib>Morgan, Iain M.</creatorcontrib><creatorcontrib>Benes, Cyril H.</creatorcontrib><creatorcontrib>Engelman, Jeffrey A.</creatorcontrib><creatorcontrib>Mossé, Yael P.</creatorcontrib><creatorcontrib>Faber, Anthony C.</creatorcontrib><title>Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>Fewer than half of children with high-risk neuroblastoma survive. Many of these tumors harbor high-level amplification of MYCN, which correlates with poor disease outcome. Using data from our large drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensitive to the BCL-2 inhibitor ABT-199. This sensitivity occurs in part through low anti-apoptotic BCL-xL expression, high pro-apoptotic NOXA expression, and paradoxical, MYCN-driven upregulation of NOXA. Screening for enhancers of ABT-199 sensitivity in MYCN-amplified neuroblastomas, we demonstrate that the Aurora Kinase A inhibitor MLN8237 combines with ABT-199 to induce widespread apoptosis. In diverse models of MYCN-amplified neuroblastoma, including a patient-derived xenograft model, this combination uniformly induced tumor shrinkage, and in multiple instances led to complete tumor regression.
[Display omitted]
•Amplified MYCN is synthetic lethal with the BCL-2 inhibitor ABT-199 in neuroblastoma•MYCN upregulates the MCL-1 inhibitor, NOXA•MYCN-amplified neuroblastomas are further sensitized to ABT-199 with MLN8237•ABT-199 with MLN8237 induce tumor regressions in MYCN-amplified neuroblastoma mice
Ham et al. show that MYCN-amplified neuroblastomas are sensitive to treatment with the BCL-2 inhibitor ABT-199 due to MYCN-driven increase of NOXA. Combination treatment with the Aurora Kinase A inhibitor MLN8237 and ABT-199 is synergistic in xenograft models of this tumor type, in part via reducing MCL-1.</description><subject>Aniline Compounds - therapeutic use</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Apoptosis - genetics</subject><subject>Cell Line, Tumor</subject><subject>Humans</subject><subject>N-Myc Proto-Oncogene Protein</subject><subject>Neuroblastoma - drug therapy</subject><subject>Neuroblastoma - genetics</subject><subject>Neuroblastoma - pathology</subject><subject>Nuclear Proteins</subject><subject>Oncogene Proteins</subject><subject>Sulfonamides - therapeutic use</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkctu1DAUhiMEoqXwBEjISzZJ7Vx8WYA0GgpFKqUSw4KV5TgnHY-SONieEX0DHpsznVLRTcXKl_P_5_Zl2WtGC0YZP90U1sIwFCU-CsoKSssn2TGTQuYVl_wp3puqyTmj8ih7EeOGopAJ9Tw7KrlsVN3w4-z32a958C6Z5PxEfE_SGshi9nPy0cX8KrgROvIN47CPfvmxvMwX4zy43uH_JWyDbwcTkx8NSZ58gB0MfiaGXPkEUyJmQvcMFvWWrEy4hoS-1RqCmW_I0o-tm25rv8ye9WaI8OruPMm-fzxbLc_zi6-fPi8XF7ltGpnyTgKAMKVVQqimM6IXLWsZdEwJrkTFDeOKMmlr6E0tJReSl6yvWQvcCkGrk-z9Ie-8bXE0i00GM-gZBzXhRnvj9MPI5Nb62u90LWrV1CUmeHuXIPifW4hJjy7uQZgJ_DZqJnC5XLLyv6Q1VwiiQWl1kNrgYwzQ33fEqN7j1ht9i1vvcWvKNOJG15t_h7n3_OWLgncHAeBKdw6CjtbBZKFzAWzSnXePFvgDJ-q-6A</recordid><startdate>20160208</startdate><enddate>20160208</enddate><creator>Ham, Jungoh</creator><creator>Costa, Carlotta</creator><creator>Sano, Renata</creator><creator>Lochmann, Timothy L.</creator><creator>Sennott, Erin M.</creator><creator>Patel, Neha U.</creator><creator>Dastur, Anahita</creator><creator>Gomez-Caraballo, Maria</creator><creator>Krytska, Kateryna</creator><creator>Hata, Aaron N.</creator><creator>Floros, Konstantinos V.</creator><creator>Hughes, Mark T.</creator><creator>Jakubik, Charles T.</creator><creator>Heisey, Daniel A.R.</creator><creator>Ferrell, Justin T.</creator><creator>Bristol, Molly L.</creator><creator>March, Ryan J.</creator><creator>Yates, Craig</creator><creator>Hicks, Mark A.</creator><creator>Nakajima, Wataru</creator><creator>Gowda, Madhu</creator><creator>Windle, Brad E.</creator><creator>Dozmorov, Mikhail G.</creator><creator>Garnett, Mathew J.</creator><creator>McDermott, Ultan</creator><creator>Harada, Hisashi</creator><creator>Taylor, Shirley M.</creator><creator>Morgan, Iain M.</creator><creator>Benes, Cyril H.</creator><creator>Engelman, Jeffrey A.</creator><creator>Mossé, Yael P.</creator><creator>Faber, Anthony C.</creator><general>Elsevier Inc</general><general>Cell Press</general><scope>6I.</scope><scope>AAFTH</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><scope>7TO</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20160208</creationdate><title>Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination</title><author>Ham, Jungoh ; Costa, Carlotta ; Sano, Renata ; Lochmann, Timothy L. ; Sennott, Erin M. ; Patel, Neha U. ; Dastur, Anahita ; Gomez-Caraballo, Maria ; Krytska, Kateryna ; Hata, Aaron N. ; Floros, Konstantinos V. ; Hughes, Mark T. ; Jakubik, Charles T. ; Heisey, Daniel A.R. ; Ferrell, Justin T. ; Bristol, Molly L. ; March, Ryan J. ; Yates, Craig ; Hicks, Mark A. ; Nakajima, Wataru ; Gowda, Madhu ; Windle, Brad E. ; Dozmorov, Mikhail G. ; Garnett, Mathew J. ; McDermott, Ultan ; Harada, Hisashi ; Taylor, Shirley M. ; Morgan, Iain M. ; Benes, Cyril H. ; Engelman, Jeffrey A. ; Mossé, Yael P. ; Faber, Anthony C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c558t-d8eee7a2c97795da7f7b1b1ed19769736a169018c4efa488678621f41be6c7703</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Aniline Compounds - therapeutic use</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Apoptosis - genetics</topic><topic>Cell Line, Tumor</topic><topic>Humans</topic><topic>N-Myc Proto-Oncogene Protein</topic><topic>Neuroblastoma - drug therapy</topic><topic>Neuroblastoma - genetics</topic><topic>Neuroblastoma - pathology</topic><topic>Nuclear Proteins</topic><topic>Oncogene Proteins</topic><topic>Sulfonamides - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ham, Jungoh</creatorcontrib><creatorcontrib>Costa, Carlotta</creatorcontrib><creatorcontrib>Sano, Renata</creatorcontrib><creatorcontrib>Lochmann, Timothy L.</creatorcontrib><creatorcontrib>Sennott, Erin M.</creatorcontrib><creatorcontrib>Patel, Neha U.</creatorcontrib><creatorcontrib>Dastur, Anahita</creatorcontrib><creatorcontrib>Gomez-Caraballo, Maria</creatorcontrib><creatorcontrib>Krytska, Kateryna</creatorcontrib><creatorcontrib>Hata, Aaron N.</creatorcontrib><creatorcontrib>Floros, Konstantinos V.</creatorcontrib><creatorcontrib>Hughes, Mark T.</creatorcontrib><creatorcontrib>Jakubik, Charles T.</creatorcontrib><creatorcontrib>Heisey, Daniel A.R.</creatorcontrib><creatorcontrib>Ferrell, Justin T.</creatorcontrib><creatorcontrib>Bristol, Molly L.</creatorcontrib><creatorcontrib>March, Ryan J.</creatorcontrib><creatorcontrib>Yates, Craig</creatorcontrib><creatorcontrib>Hicks, Mark A.</creatorcontrib><creatorcontrib>Nakajima, Wataru</creatorcontrib><creatorcontrib>Gowda, Madhu</creatorcontrib><creatorcontrib>Windle, Brad E.</creatorcontrib><creatorcontrib>Dozmorov, Mikhail G.</creatorcontrib><creatorcontrib>Garnett, Mathew J.</creatorcontrib><creatorcontrib>McDermott, Ultan</creatorcontrib><creatorcontrib>Harada, Hisashi</creatorcontrib><creatorcontrib>Taylor, Shirley M.</creatorcontrib><creatorcontrib>Morgan, Iain M.</creatorcontrib><creatorcontrib>Benes, Cyril H.</creatorcontrib><creatorcontrib>Engelman, Jeffrey A.</creatorcontrib><creatorcontrib>Mossé, Yael P.</creatorcontrib><creatorcontrib>Faber, Anthony C.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</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><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ham, Jungoh</au><au>Costa, Carlotta</au><au>Sano, Renata</au><au>Lochmann, Timothy L.</au><au>Sennott, Erin M.</au><au>Patel, Neha U.</au><au>Dastur, Anahita</au><au>Gomez-Caraballo, Maria</au><au>Krytska, Kateryna</au><au>Hata, Aaron N.</au><au>Floros, Konstantinos V.</au><au>Hughes, Mark T.</au><au>Jakubik, Charles T.</au><au>Heisey, Daniel A.R.</au><au>Ferrell, Justin T.</au><au>Bristol, Molly L.</au><au>March, Ryan J.</au><au>Yates, Craig</au><au>Hicks, Mark A.</au><au>Nakajima, Wataru</au><au>Gowda, Madhu</au><au>Windle, Brad E.</au><au>Dozmorov, Mikhail G.</au><au>Garnett, Mathew J.</au><au>McDermott, Ultan</au><au>Harada, Hisashi</au><au>Taylor, Shirley M.</au><au>Morgan, Iain M.</au><au>Benes, Cyril H.</au><au>Engelman, Jeffrey A.</au><au>Mossé, Yael P.</au><au>Faber, Anthony C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2016-02-08</date><risdate>2016</risdate><volume>29</volume><issue>2</issue><spage>159</spage><epage>172</epage><pages>159-172</pages><issn>1535-6108</issn><eissn>1878-3686</eissn><abstract>Fewer than half of children with high-risk neuroblastoma survive. Many of these tumors harbor high-level amplification of MYCN, which correlates with poor disease outcome. Using data from our large drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensitive to the BCL-2 inhibitor ABT-199. This sensitivity occurs in part through low anti-apoptotic BCL-xL expression, high pro-apoptotic NOXA expression, and paradoxical, MYCN-driven upregulation of NOXA. Screening for enhancers of ABT-199 sensitivity in MYCN-amplified neuroblastomas, we demonstrate that the Aurora Kinase A inhibitor MLN8237 combines with ABT-199 to induce widespread apoptosis. In diverse models of MYCN-amplified neuroblastoma, including a patient-derived xenograft model, this combination uniformly induced tumor shrinkage, and in multiple instances led to complete tumor regression.
[Display omitted]
•Amplified MYCN is synthetic lethal with the BCL-2 inhibitor ABT-199 in neuroblastoma•MYCN upregulates the MCL-1 inhibitor, NOXA•MYCN-amplified neuroblastomas are further sensitized to ABT-199 with MLN8237•ABT-199 with MLN8237 induce tumor regressions in MYCN-amplified neuroblastoma mice
Ham et al. show that MYCN-amplified neuroblastomas are sensitive to treatment with the BCL-2 inhibitor ABT-199 due to MYCN-driven increase of NOXA. Combination treatment with the Aurora Kinase A inhibitor MLN8237 and ABT-199 is synergistic in xenograft models of this tumor type, in part via reducing MCL-1.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>26859456</pmid><doi>10.1016/j.ccell.2016.01.002</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer cell, 2016-02, Vol.29 (2), p.159-172 |
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| language | eng |
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| source | MEDLINE; Cell Press Archives; Elsevier ScienceDirect Journals Complete; EZB Electronic Journals Library |
| subjects | Aniline Compounds - therapeutic use Antineoplastic Agents - therapeutic use Apoptosis - genetics Cell Line, Tumor Humans N-Myc Proto-Oncogene Protein Neuroblastoma - drug therapy Neuroblastoma - genetics Neuroblastoma - pathology Nuclear Proteins Oncogene Proteins Sulfonamides - therapeutic use |
| title | Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination |
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