Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer.
Identifieur interne : 000800 ( PubMed/Curation ); précédent : 000799; suivant : 000801Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer.
Auteurs : Delphine Merino [Australie] ; James R. Whittle [Australie] ; François Vaillant [Australie] ; Antonin Serrano [Australie] ; Jia-Nan Gong [Australie] ; Goknur Giner [Australie] ; Ana Leticia Maragno [France] ; Maïa Chanrion [France] ; Emilie Schneider [France] ; Bhupinder Pal [Australie] ; Xiang Li [Australie] ; Grant Dewson [Australie] ; Julius Gr Sel [Australie] ; Kevin Liu [Australie] ; Najoua Lalaoui [Australie] ; David Segal [Australie] ; Marco J. Herold [Australie] ; David C S. Huang [Australie] ; Gordon K. Smyth [Australie] ; Olivier Geneste [France] ; Guillaume Lessene [Australie] ; Jane E. Visvader [Australie] ; Geoffrey J. Lindeman [Australie]Source :
- Science translational medicine [ 1946-6242 ] ; 2017.
Abstract
The development of BH3 mimetics, which antagonize prosurvival proteins of the BCL-2 family, represents a potential breakthrough in cancer therapy. Targeting the prosurvival member MCL-1 has been an area of intense interest because it is frequently deregulated in cancer. In breast cancer, MCL-1 is often amplified, and high expression predicts poor patient outcome. We tested the MCL-1 inhibitor S63845 in breast cancer cell lines and patient-derived xenografts with high expression of MCL-1. S63845 displayed synergistic activity with docetaxel in triple-negative breast cancer and with trastuzumab or lapatinib in HER2-amplified breast cancer. Using S63845-resistant cells combined with CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated 9) technology, we identified deletion of BAK and up-regulation of prosurvival proteins as potential mechanisms that confer resistance to S63845 in breast cancer. Collectively, our findings provide a strong rationale for the clinical evaluation of MCL-1 inhibitors in breast cancer.
DOI: 10.1126/scitranslmed.aam7049
PubMed: 28768804
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<author><name sortKey="Merino, Delphine" sort="Merino, Delphine" uniqKey="Merino D" first="Delphine" last="Merino">Delphine Merino</name>
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<author><name sortKey="Vaillant, Francois" sort="Vaillant, Francois" uniqKey="Vaillant F" first="François" last="Vaillant">François Vaillant</name>
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<author><name sortKey="Gong, Jia Nan" sort="Gong, Jia Nan" uniqKey="Gong J" first="Jia-Nan" last="Gong">Jia-Nan Gong</name>
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<author><name sortKey="Giner, Goknur" sort="Giner, Goknur" uniqKey="Giner G" first="Goknur" last="Giner">Goknur Giner</name>
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<author><name sortKey="Maragno, Ana Leticia" sort="Maragno, Ana Leticia" uniqKey="Maragno A" first="Ana Leticia" last="Maragno">Ana Leticia Maragno</name>
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<author><name sortKey="Chanrion, Maia" sort="Chanrion, Maia" uniqKey="Chanrion M" first="Maïa" last="Chanrion">Maïa Chanrion</name>
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<author><name sortKey="Pal, Bhupinder" sort="Pal, Bhupinder" uniqKey="Pal B" first="Bhupinder" last="Pal">Bhupinder Pal</name>
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<author><name sortKey="Li, Xiang" sort="Li, Xiang" uniqKey="Li X" first="Xiang" last="Li">Xiang Li</name>
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<author><name sortKey="Dewson, Grant" sort="Dewson, Grant" uniqKey="Dewson G" first="Grant" last="Dewson">Grant Dewson</name>
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<author><name sortKey="Gr Sel, Julius" sort="Gr Sel, Julius" uniqKey="Gr Sel J" first="Julius" last="Gr Sel">Julius Gr Sel</name>
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<wicri:regionArea>ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052</wicri:regionArea>
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<author><name sortKey="Liu, Kevin" sort="Liu, Kevin" uniqKey="Liu K" first="Kevin" last="Liu">Kevin Liu</name>
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<country xml:lang="fr">Australie</country>
<wicri:regionArea>ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052</wicri:regionArea>
</affiliation>
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<author><name sortKey="Lalaoui, Najoua" sort="Lalaoui, Najoua" uniqKey="Lalaoui N" first="Najoua" last="Lalaoui">Najoua Lalaoui</name>
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<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010</wicri:regionArea>
</affiliation>
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<author><name sortKey="Segal, David" sort="Segal, David" uniqKey="Segal D" first="David" last="Segal">David Segal</name>
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<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Herold, Marco J" sort="Herold, Marco J" uniqKey="Herold M" first="Marco J" last="Herold">Marco J. Herold</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Huang, David C S" sort="Huang, David C S" uniqKey="Huang D" first="David C S" last="Huang">David C S. Huang</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Smyth, Gordon K" sort="Smyth, Gordon K" uniqKey="Smyth G" first="Gordon K" last="Smyth">Gordon K. Smyth</name>
<affiliation wicri:level="1"><nlm:affiliation>Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Geneste, Olivier" sort="Geneste, Olivier" uniqKey="Geneste O" first="Olivier" last="Geneste">Olivier Geneste</name>
<affiliation wicri:level="1"><nlm:affiliation>Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290</wicri:regionArea>
</affiliation>
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<author><name sortKey="Lessene, Guillaume" sort="Lessene, Guillaume" uniqKey="Lessene G" first="Guillaume" last="Lessene">Guillaume Lessene</name>
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<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010</wicri:regionArea>
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<author><name sortKey="Visvader, Jane E" sort="Visvader, Jane E" uniqKey="Visvader J" first="Jane E" last="Visvader">Jane E. Visvader</name>
<affiliation wicri:level="1"><nlm:affiliation>ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia. visvader@wehi.edu.au lindeman@wehi.edu.au.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lindeman, Geoffrey J" sort="Lindeman, Geoffrey J" uniqKey="Lindeman G" first="Geoffrey J" last="Lindeman">Geoffrey J. Lindeman</name>
<affiliation wicri:level="1"><nlm:affiliation>ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia. visvader@wehi.edu.au lindeman@wehi.edu.au.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052</wicri:regionArea>
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<series><title level="j">Science translational medicine</title>
<idno type="eISSN">1946-6242</idno>
<imprint><date when="2017" type="published">2017</date>
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<front><div type="abstract" xml:lang="en">The development of BH3 mimetics, which antagonize prosurvival proteins of the BCL-2 family, represents a potential breakthrough in cancer therapy. Targeting the prosurvival member MCL-1 has been an area of intense interest because it is frequently deregulated in cancer. In breast cancer, MCL-1 is often amplified, and high expression predicts poor patient outcome. We tested the MCL-1 inhibitor S63845 in breast cancer cell lines and patient-derived xenografts with high expression of MCL-1. S63845 displayed synergistic activity with docetaxel in triple-negative breast cancer and with trastuzumab or lapatinib in HER2-amplified breast cancer. Using S63845-resistant cells combined with CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated 9) technology, we identified deletion of BAK and up-regulation of prosurvival proteins as potential mechanisms that confer resistance to S63845 in breast cancer. Collectively, our findings provide a strong rationale for the clinical evaluation of MCL-1 inhibitors in breast cancer.</div>
</front>
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<pubmed><MedlineCitation Status="In-Process" Owner="NLM"><PMID Version="1">28768804</PMID>
<DateCreated><Year>2017</Year>
<Month>08</Month>
<Day>03</Day>
</DateCreated>
<DateRevised><Year>2017</Year>
<Month>08</Month>
<Day>03</Day>
</DateRevised>
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<JournalIssue CitedMedium="Internet"><Volume>9</Volume>
<Issue>401</Issue>
<PubDate><Year>2017</Year>
<Month>Aug</Month>
<Day>02</Day>
</PubDate>
</JournalIssue>
<Title>Science translational medicine</Title>
<ISOAbbreviation>Sci Transl Med</ISOAbbreviation>
</Journal>
<ArticleTitle>Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer.</ArticleTitle>
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<Abstract><AbstractText>The development of BH3 mimetics, which antagonize prosurvival proteins of the BCL-2 family, represents a potential breakthrough in cancer therapy. Targeting the prosurvival member MCL-1 has been an area of intense interest because it is frequently deregulated in cancer. In breast cancer, MCL-1 is often amplified, and high expression predicts poor patient outcome. We tested the MCL-1 inhibitor S63845 in breast cancer cell lines and patient-derived xenografts with high expression of MCL-1. S63845 displayed synergistic activity with docetaxel in triple-negative breast cancer and with trastuzumab or lapatinib in HER2-amplified breast cancer. Using S63845-resistant cells combined with CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated 9) technology, we identified deletion of BAK and up-regulation of prosurvival proteins as potential mechanisms that confer resistance to S63845 in breast cancer. Collectively, our findings provide a strong rationale for the clinical evaluation of MCL-1 inhibitors in breast cancer.</AbstractText>
<CopyrightInformation>Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.</CopyrightInformation>
</Abstract>
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<AffiliationInfo><Affiliation>ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
</Author>
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<ForeName>James R</ForeName>
<Initials>JR</Initials>
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<AffiliationInfo><Affiliation>ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.</Affiliation>
</AffiliationInfo>
</Author>
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<ForeName>François</ForeName>
<Initials>F</Initials>
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<AffiliationInfo><Affiliation>ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.</Affiliation>
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<AffiliationInfo><Affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
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<AffiliationInfo><Affiliation>ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
</Author>
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<ForeName>Jia-Nan</ForeName>
<Initials>JN</Initials>
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<AffiliationInfo><Affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.</Affiliation>
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</Author>
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<ForeName>Goknur</ForeName>
<Initials>G</Initials>
<AffiliationInfo><Affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.</Affiliation>
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<ForeName>Ana Leticia</ForeName>
<Initials>AL</Initials>
<AffiliationInfo><Affiliation>Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France.</Affiliation>
</AffiliationInfo>
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<Initials>M</Initials>
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<Initials>E</Initials>
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<ForeName>Bhupinder</ForeName>
<Initials>B</Initials>
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</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Li</LastName>
<ForeName>Xiang</ForeName>
<Initials>X</Initials>
<AffiliationInfo><Affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Dewson</LastName>
<ForeName>Grant</ForeName>
<Initials>G</Initials>
<AffiliationInfo><Affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Gräsel</LastName>
<ForeName>Julius</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
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<Author ValidYN="Y"><LastName>Liu</LastName>
<ForeName>Kevin</ForeName>
<Initials>K</Initials>
<AffiliationInfo><Affiliation>ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lalaoui</LastName>
<ForeName>Najoua</ForeName>
<Initials>N</Initials>
<Identifier Source="ORCID">http://orcid.org/0000-0002-0165-3324</Identifier>
<AffiliationInfo><Affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Segal</LastName>
<ForeName>David</ForeName>
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<AffiliationInfo><Affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Herold</LastName>
<ForeName>Marco J</ForeName>
<Initials>MJ</Initials>
<AffiliationInfo><Affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Molecular Genetics of Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Huang</LastName>
<ForeName>David C S</ForeName>
<Initials>DCS</Initials>
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<AffiliationInfo><Affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.</Affiliation>
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</Author>
<Author ValidYN="Y"><LastName>Smyth</LastName>
<ForeName>Gordon K</ForeName>
<Initials>GK</Initials>
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<AffiliationInfo><Affiliation>Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>School of Mathematics and Statistics, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Geneste</LastName>
<ForeName>Olivier</ForeName>
<Initials>O</Initials>
<AffiliationInfo><Affiliation>Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France.</Affiliation>
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<Author ValidYN="Y"><LastName>Lessene</LastName>
<ForeName>Guillaume</ForeName>
<Initials>G</Initials>
<Identifier Source="ORCID">http://orcid.org/0000-0002-1193-8147</Identifier>
<AffiliationInfo><Affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Visvader</LastName>
<ForeName>Jane E</ForeName>
<Initials>JE</Initials>
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<AffiliationInfo><Affiliation>ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia. visvader@wehi.edu.au lindeman@wehi.edu.au.</Affiliation>
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<AffiliationInfo><Affiliation>Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
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</Author>
<Author ValidYN="Y"><LastName>Lindeman</LastName>
<ForeName>Geoffrey J</ForeName>
<Initials>GJ</Initials>
<AffiliationInfo><Affiliation>ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia. visvader@wehi.edu.au lindeman@wehi.edu.au.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Medicine, University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Parkville Familial Cancer Centre, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, Victoria 3050, Australia.</Affiliation>
</AffiliationInfo>
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<Month>04</Month>
<Day>13</Day>
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