Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia
ABT-199, a potent and selective small-molecule antagonist of BCL-2, is being clinically vetted as pharmacotherapy for the treatment of acute myeloid leukemia (AML). However, given that prolonged monotherapy tends to beget resistance, we sought to investigate the means by which resistance to ABT-199...
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| creator | Lin, Kevin H. Winter, Peter S. Xie, Abigail Roth, Cullen Martz, Colin A. Stein, Elizabeth M. Anderson, Gray R. Tingley, Jennifer P. Wood, Kris C. |
| description | ABT-199, a potent and selective small-molecule antagonist of BCL-2, is being clinically vetted as pharmacotherapy for the treatment of acute myeloid leukemia (AML). However, given that prolonged monotherapy tends to beget resistance, we sought to investigate the means by which resistance to ABT-199 might arise in AML and the extent to which those mechanisms might be preempted. Here we used a pathway-activating genetic screen to nominate MCL-1 and BCL-X
L
as potential nodes of resistance. We then characterized a panel of ABT-199-resistant myeloid leukemia cell lines derived through chronic exposure to ABT-199 and found that acquired drug resistance is indeed driven by the upregulation of MCL-1 and BCL-X
L
. By targeting MCL-1 and BCL-X
L
, resistant AML cell lines could be resensitized to ABT-199. Further, preemptively targeting MCL-1 and/or BCL-X
L
alongside administration of ABT-199 was capable of delaying or forestalling the acquisition of drug resistance. Collectively, these data suggest that in AML, (1) the selection of initial therapy dynamically templates the landscape of acquired resistance via modulation of MCL-1/BCL-X
L
and (2) appropriate selection of initial therapy may delay or altogether forestall the acquisition of resistance to ABT-199. |
| doi_str_mv | 10.1038/srep27696 |
| format | Article |
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L
as potential nodes of resistance. We then characterized a panel of ABT-199-resistant myeloid leukemia cell lines derived through chronic exposure to ABT-199 and found that acquired drug resistance is indeed driven by the upregulation of MCL-1 and BCL-X
L
. By targeting MCL-1 and BCL-X
L
, resistant AML cell lines could be resensitized to ABT-199. Further, preemptively targeting MCL-1 and/or BCL-X
L
alongside administration of ABT-199 was capable of delaying or forestalling the acquisition of drug resistance. Collectively, these data suggest that in AML, (1) the selection of initial therapy dynamically templates the landscape of acquired resistance via modulation of MCL-1/BCL-X
L
and (2) appropriate selection of initial therapy may delay or altogether forestall the acquisition of resistance to ABT-199.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep27696</identifier><identifier>PMID: 27283158</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/1 ; 13/106 ; 13/95 ; 38/47 ; 692/4028/67/1059/2326 ; 692/4028/67/1059/602 ; 692/4028/67/1990/283/1897 ; Acute myeloid leukemia ; Antineoplastic Agents - pharmacology ; Apoptosis ; Bcl-2 protein ; Bcl-x protein ; bcl-X Protein - genetics ; bcl-X Protein - metabolism ; Bridged Bicyclo Compounds, Heterocyclic - pharmacology ; Cell Line, Tumor ; Chronic exposure ; Drug dosages ; Drug resistance ; Drug Resistance, Neoplasm ; Drug therapy ; Experiments ; Genetic screening ; Humanities and Social Sciences ; Humans ; Leukemia ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - metabolism ; Mcl-1 protein ; multidisciplinary ; Myeloid Cell Leukemia Sequence 1 Protein - genetics ; Myeloid Cell Leukemia Sequence 1 Protein - metabolism ; Peptides ; Science ; Sulfonamides - pharmacology ; Tumor cell lines</subject><ispartof>Scientific reports, 2016-06, Vol.6 (1), p.27696-27696, Article 27696</ispartof><rights>The Author(s) 2016</rights><rights>Copyright Nature Publishing Group Jun 2016</rights><rights>The Author(s) 2016. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Copyright © 2016, Macmillan Publishers Limited 2016 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c466t-fdfb3b89553853fd0ffa89c6d35cc4cf08e50139a783a03c4eaea2e2501548273</citedby><cites>FETCH-LOGICAL-c466t-fdfb3b89553853fd0ffa89c6d35cc4cf08e50139a783a03c4eaea2e2501548273</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/PMC4901329/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4901329/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27283158$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lin, Kevin H.</creatorcontrib><creatorcontrib>Winter, Peter S.</creatorcontrib><creatorcontrib>Xie, Abigail</creatorcontrib><creatorcontrib>Roth, Cullen</creatorcontrib><creatorcontrib>Martz, Colin A.</creatorcontrib><creatorcontrib>Stein, Elizabeth M.</creatorcontrib><creatorcontrib>Anderson, Gray R.</creatorcontrib><creatorcontrib>Tingley, Jennifer P.</creatorcontrib><creatorcontrib>Wood, Kris C.</creatorcontrib><title>Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>ABT-199, a potent and selective small-molecule antagonist of BCL-2, is being clinically vetted as pharmacotherapy for the treatment of acute myeloid leukemia (AML). However, given that prolonged monotherapy tends to beget resistance, we sought to investigate the means by which resistance to ABT-199 might arise in AML and the extent to which those mechanisms might be preempted. Here we used a pathway-activating genetic screen to nominate MCL-1 and BCL-X
L
as potential nodes of resistance. We then characterized a panel of ABT-199-resistant myeloid leukemia cell lines derived through chronic exposure to ABT-199 and found that acquired drug resistance is indeed driven by the upregulation of MCL-1 and BCL-X
L
. By targeting MCL-1 and BCL-X
L
, resistant AML cell lines could be resensitized to ABT-199. Further, preemptively targeting MCL-1 and/or BCL-X
L
alongside administration of ABT-199 was capable of delaying or forestalling the acquisition of drug resistance. Collectively, these data suggest that in AML, (1) the selection of initial therapy dynamically templates the landscape of acquired resistance via modulation of MCL-1/BCL-X
L
and (2) appropriate selection of initial therapy may delay or altogether forestall the acquisition of resistance to ABT-199.</description><subject>13</subject><subject>13/1</subject><subject>13/106</subject><subject>13/95</subject><subject>38/47</subject><subject>692/4028/67/1059/2326</subject><subject>692/4028/67/1059/602</subject><subject>692/4028/67/1990/283/1897</subject><subject>Acute myeloid leukemia</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Bcl-2 protein</subject><subject>Bcl-x protein</subject><subject>bcl-X Protein - genetics</subject><subject>bcl-X Protein - metabolism</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Chronic exposure</subject><subject>Drug dosages</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm</subject><subject>Drug therapy</subject><subject>Experiments</subject><subject>Genetic screening</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - metabolism</subject><subject>Mcl-1 protein</subject><subject>multidisciplinary</subject><subject>Myeloid Cell Leukemia Sequence 1 Protein - genetics</subject><subject>Myeloid Cell Leukemia Sequence 1 Protein - metabolism</subject><subject>Peptides</subject><subject>Science</subject><subject>Sulfonamides - pharmacology</subject><subject>Tumor cell lines</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kV1rFDEUhoMottRe-Ack4I0KY_M5k9wI28WqMEWQFbwL2czJNnU22SYzQv-9ka3LqmAukpDz8CQnL0LPKXlLCVcXJcOOda1uH6FTRoRsGGfs8dH-BJ2XckvqkEwLqp-iE9YxxalUp2hY2byBKcQNvl72Db24rPO3Hl-lDGWy41jwdAN44e7mUMIUUsTJ4y9QQq1GB3hKeHG5aqjWOMTKzRPg63sYUxhwD_N32Ab7DD3xdixw_rCeoa9X71fLj03_-cOn5aJvnGjbqfGDX_O10lJyJbkfiPdWadcOXDonnCcKJKFc205xS7gTYMEyYPVQCsU6fobe7b27eb2FwUGcsh3NLoetzfcm2WD-rMRwYzbphxG6epmuglcPgpzu5voBZhuKg3G0EdJcDO20VB2Rmlf05V_obZpzrO0Z1kqhFdNa_I-qrpZ1UmpVqdd7yuVUap7-8GRKzK-QzSHkyr447vFA_o60Am_2QKmluIF8dOU_tp9GWK5J</recordid><startdate>20160610</startdate><enddate>20160610</enddate><creator>Lin, Kevin H.</creator><creator>Winter, Peter S.</creator><creator>Xie, Abigail</creator><creator>Roth, Cullen</creator><creator>Martz, Colin A.</creator><creator>Stein, Elizabeth M.</creator><creator>Anderson, Gray R.</creator><creator>Tingley, Jennifer P.</creator><creator>Wood, Kris C.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160610</creationdate><title>Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia</title><author>Lin, Kevin H. ; Winter, Peter S. ; Xie, Abigail ; Roth, Cullen ; Martz, Colin A. ; Stein, Elizabeth M. ; Anderson, Gray R. ; Tingley, Jennifer P. ; Wood, Kris C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c466t-fdfb3b89553853fd0ffa89c6d35cc4cf08e50139a783a03c4eaea2e2501548273</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>13</topic><topic>13/1</topic><topic>13/106</topic><topic>13/95</topic><topic>38/47</topic><topic>692/4028/67/1059/2326</topic><topic>692/4028/67/1059/602</topic><topic>692/4028/67/1990/283/1897</topic><topic>Acute myeloid leukemia</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Bcl-2 protein</topic><topic>Bcl-x protein</topic><topic>bcl-X Protein - genetics</topic><topic>bcl-X Protein - metabolism</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Chronic exposure</topic><topic>Drug dosages</topic><topic>Drug resistance</topic><topic>Drug Resistance, Neoplasm</topic><topic>Drug therapy</topic><topic>Experiments</topic><topic>Genetic screening</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Leukemia</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>Leukemia, Myeloid, Acute - metabolism</topic><topic>Mcl-1 protein</topic><topic>multidisciplinary</topic><topic>Myeloid Cell Leukemia Sequence 1 Protein - genetics</topic><topic>Myeloid Cell Leukemia Sequence 1 Protein - metabolism</topic><topic>Peptides</topic><topic>Science</topic><topic>Sulfonamides - pharmacology</topic><topic>Tumor cell lines</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lin, Kevin H.</creatorcontrib><creatorcontrib>Winter, Peter S.</creatorcontrib><creatorcontrib>Xie, Abigail</creatorcontrib><creatorcontrib>Roth, Cullen</creatorcontrib><creatorcontrib>Martz, Colin A.</creatorcontrib><creatorcontrib>Stein, Elizabeth M.</creatorcontrib><creatorcontrib>Anderson, Gray R.</creatorcontrib><creatorcontrib>Tingley, Jennifer P.</creatorcontrib><creatorcontrib>Wood, Kris C.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lin, Kevin H.</au><au>Winter, Peter S.</au><au>Xie, Abigail</au><au>Roth, Cullen</au><au>Martz, Colin A.</au><au>Stein, Elizabeth M.</au><au>Anderson, Gray R.</au><au>Tingley, Jennifer P.</au><au>Wood, Kris C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2016-06-10</date><risdate>2016</risdate><volume>6</volume><issue>1</issue><spage>27696</spage><epage>27696</epage><pages>27696-27696</pages><artnum>27696</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>ABT-199, a potent and selective small-molecule antagonist of BCL-2, is being clinically vetted as pharmacotherapy for the treatment of acute myeloid leukemia (AML). However, given that prolonged monotherapy tends to beget resistance, we sought to investigate the means by which resistance to ABT-199 might arise in AML and the extent to which those mechanisms might be preempted. Here we used a pathway-activating genetic screen to nominate MCL-1 and BCL-X
L
as potential nodes of resistance. We then characterized a panel of ABT-199-resistant myeloid leukemia cell lines derived through chronic exposure to ABT-199 and found that acquired drug resistance is indeed driven by the upregulation of MCL-1 and BCL-X
L
. By targeting MCL-1 and BCL-X
L
, resistant AML cell lines could be resensitized to ABT-199. Further, preemptively targeting MCL-1 and/or BCL-X
L
alongside administration of ABT-199 was capable of delaying or forestalling the acquisition of drug resistance. Collectively, these data suggest that in AML, (1) the selection of initial therapy dynamically templates the landscape of acquired resistance via modulation of MCL-1/BCL-X
L
and (2) appropriate selection of initial therapy may delay or altogether forestall the acquisition of resistance to ABT-199.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27283158</pmid><doi>10.1038/srep27696</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Nature Free; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry; Springer Nature OA Free Journals |
| subjects | 13 13/1 13/106 13/95 38/47 692/4028/67/1059/2326 692/4028/67/1059/602 692/4028/67/1990/283/1897 Acute myeloid leukemia Antineoplastic Agents - pharmacology Apoptosis Bcl-2 protein Bcl-x protein bcl-X Protein - genetics bcl-X Protein - metabolism Bridged Bicyclo Compounds, Heterocyclic - pharmacology Cell Line, Tumor Chronic exposure Drug dosages Drug resistance Drug Resistance, Neoplasm Drug therapy Experiments Genetic screening Humanities and Social Sciences Humans Leukemia Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - metabolism Mcl-1 protein multidisciplinary Myeloid Cell Leukemia Sequence 1 Protein - genetics Myeloid Cell Leukemia Sequence 1 Protein - metabolism Peptides Science Sulfonamides - pharmacology Tumor cell lines |
| title | Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia |
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