Mitochondrial Dysfunction Is a Driver of SP-2509 Drug Resistance in Ewing Sarcoma
Expression of the fusion oncoprotein EWS/FLI causes Ewing sarcoma, an aggressive pediatric tumor characterized by widespread epigenetic deregulation. These epigenetic changes are targeted by novel lysine-specific demethylase-1 (LSD1) inhibitors, which are currently in early-phase clinical trials. Si...
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Veröffentlicht in: | Molecular cancer research 2022-07, Vol.20 (7), p.1035-1046 |
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creator | Tokarsky, E John Crow, Jesse C Guenther, Lillian M Sherman, John Taslim, Cenny Alexe, Gabriela Pishas, Kathleen I Rask, Galen Justis, Blake S Kasumova, Ana Stegmaier, Kimberly Lessnick, Stephen L Theisen, Emily R |
description | Expression of the fusion oncoprotein EWS/FLI causes Ewing sarcoma, an aggressive pediatric tumor characterized by widespread epigenetic deregulation. These epigenetic changes are targeted by novel lysine-specific demethylase-1 (LSD1) inhibitors, which are currently in early-phase clinical trials. Single-agent-targeted therapy often induces resistance, and successful clinical development requires knowledge of resistance mechanisms, enabling the design of effective combination strategies. Here, we used a genome-scale CRISPR-Cas9 loss-of-function screen to identify genes whose knockout (KO) conferred resistance to the LSD1 inhibitor SP-2509 in Ewing sarcoma cell lines. Multiple genes required for mitochondrial electron transport chain (ETC) complexes III and IV function were hits in our screen. We validated this finding using genetic and chemical approaches, including CRISPR KO, ETC inhibitors, and mitochondrial depletion. Further global transcriptional profiling revealed that altered complex III/IV function disrupted the oncogenic program mediated by EWS/FLI and LSD1 and blunted the transcriptomic response to SP-2509.
These findings demonstrate that mitochondrial dysfunction modulates SP-2509 efficacy and suggest that new therapeutic strategies combining LSD1 with agents that prevent mitochondrial dysfunction may benefit patients with this aggressive malignancy. |
doi_str_mv | 10.1158/1541-7786.MCR-22-0027 |
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These findings demonstrate that mitochondrial dysfunction modulates SP-2509 efficacy and suggest that new therapeutic strategies combining LSD1 with agents that prevent mitochondrial dysfunction may benefit patients with this aggressive malignancy.</description><identifier>ISSN: 1541-7786</identifier><identifier>EISSN: 1557-3125</identifier><identifier>DOI: 10.1158/1541-7786.MCR-22-0027</identifier><identifier>PMID: 35298000</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Bone Neoplasms - drug therapy ; Bone Neoplasms - genetics ; Bone Neoplasms - pathology ; Cancer Genes and Networks ; Cell Line, Tumor ; Child ; Drug Resistance ; Gene Expression Regulation, Neoplastic ; Histone Demethylases - genetics ; Histone Demethylases - metabolism ; Humans ; Mitochondria - metabolism ; Oncogene Proteins, Fusion - genetics ; Oncogene Proteins, Fusion - metabolism ; Proto-Oncogene Protein c-fli-1 - genetics ; Proto-Oncogene Protein c-fli-1 - metabolism ; RNA-Binding Protein EWS - genetics ; RNA-Binding Protein EWS - metabolism ; Sarcoma, Ewing - drug therapy ; Sarcoma, Ewing - genetics ; Sarcoma, Ewing - pathology</subject><ispartof>Molecular cancer research, 2022-07, Vol.20 (7), p.1035-1046</ispartof><rights>2022 The Authors; Published by the American Association for Cancer Research.</rights><rights>2022 The Authors; Published by the American Association for Cancer Research 2022 American Association for Cancer Research</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c411t-68ccd5a1aa8cd13dc53448b48d72cbd01e22295b4339906b0cba82fe7aba46de3</citedby><cites>FETCH-LOGICAL-c411t-68ccd5a1aa8cd13dc53448b48d72cbd01e22295b4339906b0cba82fe7aba46de3</cites><orcidid>0000-0003-2923-1198 ; 0000-0003-4861-2412 ; 0000-0001-9645-4434 ; 0000-0002-5668-6297 ; 0000-0001-7863-807X ; 0000-0003-3302-9099 ; 0000-0002-5906-7504</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35298000$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tokarsky, E John</creatorcontrib><creatorcontrib>Crow, Jesse C</creatorcontrib><creatorcontrib>Guenther, Lillian M</creatorcontrib><creatorcontrib>Sherman, John</creatorcontrib><creatorcontrib>Taslim, Cenny</creatorcontrib><creatorcontrib>Alexe, Gabriela</creatorcontrib><creatorcontrib>Pishas, Kathleen I</creatorcontrib><creatorcontrib>Rask, Galen</creatorcontrib><creatorcontrib>Justis, Blake S</creatorcontrib><creatorcontrib>Kasumova, Ana</creatorcontrib><creatorcontrib>Stegmaier, Kimberly</creatorcontrib><creatorcontrib>Lessnick, Stephen L</creatorcontrib><creatorcontrib>Theisen, Emily R</creatorcontrib><title>Mitochondrial Dysfunction Is a Driver of SP-2509 Drug Resistance in Ewing Sarcoma</title><title>Molecular cancer research</title><addtitle>Mol Cancer Res</addtitle><description>Expression of the fusion oncoprotein EWS/FLI causes Ewing sarcoma, an aggressive pediatric tumor characterized by widespread epigenetic deregulation. These epigenetic changes are targeted by novel lysine-specific demethylase-1 (LSD1) inhibitors, which are currently in early-phase clinical trials. Single-agent-targeted therapy often induces resistance, and successful clinical development requires knowledge of resistance mechanisms, enabling the design of effective combination strategies. Here, we used a genome-scale CRISPR-Cas9 loss-of-function screen to identify genes whose knockout (KO) conferred resistance to the LSD1 inhibitor SP-2509 in Ewing sarcoma cell lines. Multiple genes required for mitochondrial electron transport chain (ETC) complexes III and IV function were hits in our screen. We validated this finding using genetic and chemical approaches, including CRISPR KO, ETC inhibitors, and mitochondrial depletion. Further global transcriptional profiling revealed that altered complex III/IV function disrupted the oncogenic program mediated by EWS/FLI and LSD1 and blunted the transcriptomic response to SP-2509.
These findings demonstrate that mitochondrial dysfunction modulates SP-2509 efficacy and suggest that new therapeutic strategies combining LSD1 with agents that prevent mitochondrial dysfunction may benefit patients with this aggressive malignancy.</description><subject>Bone Neoplasms - drug therapy</subject><subject>Bone Neoplasms - genetics</subject><subject>Bone Neoplasms - pathology</subject><subject>Cancer Genes and Networks</subject><subject>Cell Line, Tumor</subject><subject>Child</subject><subject>Drug Resistance</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Histone Demethylases - genetics</subject><subject>Histone Demethylases - metabolism</subject><subject>Humans</subject><subject>Mitochondria - metabolism</subject><subject>Oncogene Proteins, Fusion - genetics</subject><subject>Oncogene Proteins, Fusion - metabolism</subject><subject>Proto-Oncogene Protein c-fli-1 - genetics</subject><subject>Proto-Oncogene Protein c-fli-1 - metabolism</subject><subject>RNA-Binding Protein EWS - genetics</subject><subject>RNA-Binding Protein EWS - metabolism</subject><subject>Sarcoma, Ewing - drug therapy</subject><subject>Sarcoma, Ewing - genetics</subject><subject>Sarcoma, Ewing - pathology</subject><issn>1541-7786</issn><issn>1557-3125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUctOwzAQtBCIR-ETQD5ySbHXduJckFDLSwLxPluO4xSj1AY7AfH3JKIgOO1qd2Z2NYPQPiVTSoU8ooLTrChkPr2e3WcAGSFQrKFtKkSRMQpifexXmC20k9LLgCC0yDfRFhNQSkLINrq7dl0wz8HX0ekWzz9T03vTueDxZcIaz6N7txGHBj_cZiBIOUz6Bb63yaVOe2Ox8_j0w_kFftDRhKXeRRuNbpPdW9UJejo7fZxdZFc355ezk6vMcEq7LJfG1EJTraWpKauNYJzLisu6AFPVhFoAKEXFGStLklfEVFpCYwtdaZ7Xlk3Q8bfua18tbW2s76Ju1Wt0Sx0_VdBO_d9496wW4V2VIDkv-CBwuBKI4a23qVNLl4xtW-1t6JOCnBMGQEk5QMU31MSQUrTN7xlK1BiHGq1Wo9VqiEMBqDGOgXfw98df1o__7AtbtoaI</recordid><startdate>20220706</startdate><enddate>20220706</enddate><creator>Tokarsky, E John</creator><creator>Crow, Jesse C</creator><creator>Guenther, Lillian M</creator><creator>Sherman, John</creator><creator>Taslim, Cenny</creator><creator>Alexe, Gabriela</creator><creator>Pishas, Kathleen I</creator><creator>Rask, Galen</creator><creator>Justis, Blake S</creator><creator>Kasumova, Ana</creator><creator>Stegmaier, Kimberly</creator><creator>Lessnick, Stephen L</creator><creator>Theisen, Emily R</creator><general>American Association for Cancer Research</general><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>5PM</scope><orcidid>https://orcid.org/0000-0003-2923-1198</orcidid><orcidid>https://orcid.org/0000-0003-4861-2412</orcidid><orcidid>https://orcid.org/0000-0001-9645-4434</orcidid><orcidid>https://orcid.org/0000-0002-5668-6297</orcidid><orcidid>https://orcid.org/0000-0001-7863-807X</orcidid><orcidid>https://orcid.org/0000-0003-3302-9099</orcidid><orcidid>https://orcid.org/0000-0002-5906-7504</orcidid></search><sort><creationdate>20220706</creationdate><title>Mitochondrial Dysfunction Is a Driver of SP-2509 Drug Resistance in Ewing Sarcoma</title><author>Tokarsky, E John ; Crow, Jesse C ; Guenther, Lillian M ; Sherman, John ; Taslim, Cenny ; Alexe, Gabriela ; Pishas, Kathleen I ; Rask, Galen ; Justis, Blake S ; Kasumova, Ana ; Stegmaier, Kimberly ; Lessnick, Stephen L ; Theisen, Emily R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c411t-68ccd5a1aa8cd13dc53448b48d72cbd01e22295b4339906b0cba82fe7aba46de3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Bone Neoplasms - drug therapy</topic><topic>Bone Neoplasms - genetics</topic><topic>Bone Neoplasms - pathology</topic><topic>Cancer Genes and Networks</topic><topic>Cell Line, Tumor</topic><topic>Child</topic><topic>Drug Resistance</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Histone Demethylases - genetics</topic><topic>Histone Demethylases - metabolism</topic><topic>Humans</topic><topic>Mitochondria - metabolism</topic><topic>Oncogene Proteins, Fusion - genetics</topic><topic>Oncogene Proteins, Fusion - metabolism</topic><topic>Proto-Oncogene Protein c-fli-1 - genetics</topic><topic>Proto-Oncogene Protein c-fli-1 - metabolism</topic><topic>RNA-Binding Protein EWS - genetics</topic><topic>RNA-Binding Protein EWS - metabolism</topic><topic>Sarcoma, Ewing - drug therapy</topic><topic>Sarcoma, Ewing - genetics</topic><topic>Sarcoma, Ewing - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tokarsky, E John</creatorcontrib><creatorcontrib>Crow, Jesse C</creatorcontrib><creatorcontrib>Guenther, Lillian M</creatorcontrib><creatorcontrib>Sherman, John</creatorcontrib><creatorcontrib>Taslim, Cenny</creatorcontrib><creatorcontrib>Alexe, Gabriela</creatorcontrib><creatorcontrib>Pishas, Kathleen I</creatorcontrib><creatorcontrib>Rask, Galen</creatorcontrib><creatorcontrib>Justis, Blake S</creatorcontrib><creatorcontrib>Kasumova, Ana</creatorcontrib><creatorcontrib>Stegmaier, Kimberly</creatorcontrib><creatorcontrib>Lessnick, Stephen L</creatorcontrib><creatorcontrib>Theisen, Emily R</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tokarsky, E John</au><au>Crow, Jesse C</au><au>Guenther, Lillian M</au><au>Sherman, John</au><au>Taslim, Cenny</au><au>Alexe, Gabriela</au><au>Pishas, Kathleen I</au><au>Rask, Galen</au><au>Justis, Blake S</au><au>Kasumova, Ana</au><au>Stegmaier, Kimberly</au><au>Lessnick, Stephen L</au><au>Theisen, Emily R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mitochondrial Dysfunction Is a Driver of SP-2509 Drug Resistance in Ewing Sarcoma</atitle><jtitle>Molecular cancer research</jtitle><addtitle>Mol Cancer Res</addtitle><date>2022-07-06</date><risdate>2022</risdate><volume>20</volume><issue>7</issue><spage>1035</spage><epage>1046</epage><pages>1035-1046</pages><issn>1541-7786</issn><eissn>1557-3125</eissn><abstract>Expression of the fusion oncoprotein EWS/FLI causes Ewing sarcoma, an aggressive pediatric tumor characterized by widespread epigenetic deregulation. These epigenetic changes are targeted by novel lysine-specific demethylase-1 (LSD1) inhibitors, which are currently in early-phase clinical trials. Single-agent-targeted therapy often induces resistance, and successful clinical development requires knowledge of resistance mechanisms, enabling the design of effective combination strategies. Here, we used a genome-scale CRISPR-Cas9 loss-of-function screen to identify genes whose knockout (KO) conferred resistance to the LSD1 inhibitor SP-2509 in Ewing sarcoma cell lines. Multiple genes required for mitochondrial electron transport chain (ETC) complexes III and IV function were hits in our screen. We validated this finding using genetic and chemical approaches, including CRISPR KO, ETC inhibitors, and mitochondrial depletion. Further global transcriptional profiling revealed that altered complex III/IV function disrupted the oncogenic program mediated by EWS/FLI and LSD1 and blunted the transcriptomic response to SP-2509.
These findings demonstrate that mitochondrial dysfunction modulates SP-2509 efficacy and suggest that new therapeutic strategies combining LSD1 with agents that prevent mitochondrial dysfunction may benefit patients with this aggressive malignancy.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>35298000</pmid><doi>10.1158/1541-7786.MCR-22-0027</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-2923-1198</orcidid><orcidid>https://orcid.org/0000-0003-4861-2412</orcidid><orcidid>https://orcid.org/0000-0001-9645-4434</orcidid><orcidid>https://orcid.org/0000-0002-5668-6297</orcidid><orcidid>https://orcid.org/0000-0001-7863-807X</orcidid><orcidid>https://orcid.org/0000-0003-3302-9099</orcidid><orcidid>https://orcid.org/0000-0002-5906-7504</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Bone Neoplasms - drug therapy Bone Neoplasms - genetics Bone Neoplasms - pathology Cancer Genes and Networks Cell Line, Tumor Child Drug Resistance Gene Expression Regulation, Neoplastic Histone Demethylases - genetics Histone Demethylases - metabolism Humans Mitochondria - metabolism Oncogene Proteins, Fusion - genetics Oncogene Proteins, Fusion - metabolism Proto-Oncogene Protein c-fli-1 - genetics Proto-Oncogene Protein c-fli-1 - metabolism RNA-Binding Protein EWS - genetics RNA-Binding Protein EWS - metabolism Sarcoma, Ewing - drug therapy Sarcoma, Ewing - genetics Sarcoma, Ewing - pathology |
title | Mitochondrial Dysfunction Is a Driver of SP-2509 Drug Resistance in Ewing Sarcoma |
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