Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma
The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively ta...
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| Veröffentlicht in: | The Journal of clinical investigation 2020-11, Vol.130 (11), p.5875-5892 |
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| creator | Poon, Evon Liang, Tong Jamin, Yann Walz, Susanne Kwok, Colin Hakkert, Anne Barker, Karen Urban, Zuzanna Thway, Khin Zeid, Rhamy Hallsworth, Albert Box, Gary Ebus, Marli E Licciardello, Marco P Sbirkov, Yordan Lazaro, Glori Calton, Elizabeth Costa, Barbara M Valenti, Melanie Brandon, Alexis De Haven Webber, Hannah Tardif, Nicolas Almeida, Gilberto S Christova, Rossitza Boysen, Gunther Richards, Mark W Barone, Giuseppe d, Anthony Bayliss, Richard Clarke, Paul A DE BONO, Johann Gray, Nathanael S Blagg, Julian Robinson, Simon P Eccles, Suzanne A Zheleva, Daniella Bradner, James E Molenaar, Jan Vivanco, Igor Eilers, Martin Workman, Paul Lin, Charles Y Chesler, Louis |
| description | The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 - a component of the transcription elongation complex P-TEFb - bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma. |
| doi_str_mv | 10.1172/JCM34132. |
| format | Article |
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Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 - a component of the transcription elongation complex P-TEFb - bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCM34132.</identifier><language>eng</language><publisher>Ann Arbor: American Society for Clinical Investigation</publisher><subject>Apoptosis ; Biomedical research ; Cell cycle ; Cell growth ; Cyclin-dependent kinase 2 ; Enhancers ; Gene expression ; Kinases ; Mesenchyme ; Myc protein ; Neuroblastoma ; Pediatrics ; Phosphorylation ; Proteins ; RNA polymerase ; Temozolomide ; Transcription elongation ; Transcription factors ; Tumors</subject><ispartof>The Journal of clinical investigation, 2020-11, Vol.130 (11), p.5875-5892</ispartof><rights>Copyright American Society for Clinical Investigation Nov 2020</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27926,27927</link.rule.ids></links><search><creatorcontrib>Poon, Evon</creatorcontrib><creatorcontrib>Liang, Tong</creatorcontrib><creatorcontrib>Jamin, Yann</creatorcontrib><creatorcontrib>Walz, Susanne</creatorcontrib><creatorcontrib>Kwok, Colin</creatorcontrib><creatorcontrib>Hakkert, Anne</creatorcontrib><creatorcontrib>Barker, Karen</creatorcontrib><creatorcontrib>Urban, Zuzanna</creatorcontrib><creatorcontrib>Thway, Khin</creatorcontrib><creatorcontrib>Zeid, Rhamy</creatorcontrib><creatorcontrib>Hallsworth, Albert</creatorcontrib><creatorcontrib>Box, Gary</creatorcontrib><creatorcontrib>Ebus, Marli E</creatorcontrib><creatorcontrib>Licciardello, Marco P</creatorcontrib><creatorcontrib>Sbirkov, Yordan</creatorcontrib><creatorcontrib>Lazaro, Glori</creatorcontrib><creatorcontrib>Calton, Elizabeth</creatorcontrib><creatorcontrib>Costa, Barbara M</creatorcontrib><creatorcontrib>Valenti, Melanie</creatorcontrib><creatorcontrib>Brandon, Alexis De Haven</creatorcontrib><creatorcontrib>Webber, Hannah</creatorcontrib><creatorcontrib>Tardif, Nicolas</creatorcontrib><creatorcontrib>Almeida, Gilberto S</creatorcontrib><creatorcontrib>Christova, Rossitza</creatorcontrib><creatorcontrib>Boysen, Gunther</creatorcontrib><creatorcontrib>Richards, Mark W</creatorcontrib><creatorcontrib>Barone, Giuseppe</creatorcontrib><creatorcontrib>d, Anthony</creatorcontrib><creatorcontrib>Bayliss, Richard</creatorcontrib><creatorcontrib>Clarke, Paul A</creatorcontrib><creatorcontrib>DE BONO, Johann</creatorcontrib><creatorcontrib>Gray, Nathanael S</creatorcontrib><creatorcontrib>Blagg, Julian</creatorcontrib><creatorcontrib>Robinson, Simon P</creatorcontrib><creatorcontrib>Eccles, Suzanne A</creatorcontrib><creatorcontrib>Zheleva, Daniella</creatorcontrib><creatorcontrib>Bradner, James E</creatorcontrib><creatorcontrib>Molenaar, Jan</creatorcontrib><creatorcontrib>Vivanco, Igor</creatorcontrib><creatorcontrib>Eilers, Martin</creatorcontrib><creatorcontrib>Workman, Paul</creatorcontrib><creatorcontrib>Lin, Charles Y</creatorcontrib><creatorcontrib>Chesler, Louis</creatorcontrib><title>Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma</title><title>The Journal of clinical investigation</title><description>The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 - a component of the transcription elongation complex P-TEFb - bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma.</description><subject>Apoptosis</subject><subject>Biomedical research</subject><subject>Cell cycle</subject><subject>Cell growth</subject><subject>Cyclin-dependent kinase 2</subject><subject>Enhancers</subject><subject>Gene expression</subject><subject>Kinases</subject><subject>Mesenchyme</subject><subject>Myc protein</subject><subject>Neuroblastoma</subject><subject>Pediatrics</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>RNA polymerase</subject><subject>Temozolomide</subject><subject>Transcription elongation</subject><subject>Transcription 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CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma</atitle><jtitle>The Journal of clinical investigation</jtitle><date>2020-11-01</date><risdate>2020</risdate><volume>130</volume><issue>11</issue><spage>5875</spage><epage>5892</epage><pages>5875-5892</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 - a component of the transcription elongation complex P-TEFb - bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma.</abstract><cop>Ann Arbor</cop><pub>American Society for Clinical Investigation</pub><doi>10.1172/JCM34132.</doi></addata></record> |
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| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Apoptosis Biomedical research Cell cycle Cell growth Cyclin-dependent kinase 2 Enhancers Gene expression Kinases Mesenchyme Myc protein Neuroblastoma Pediatrics Phosphorylation Proteins RNA polymerase Temozolomide Transcription elongation Transcription factors Tumors |
| title | Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma |
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