Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma

Evon Poon; Tong Liang; Yann Jamin; Susanne Walz; Colin Kwok; Anne Hakkert; Karen Barker; Zuzanna Urban; Khin Thway; Rhamy Zeid; Albert Hallsworth; Gary Box; Marli E. Ebus; Marco P. Licciardello; Yordan Sbirkov; Glori Lazaro; Elizabeth Calton; Barbara M. Costa; Melanie Valenti; Alexis de Haven Brandon; Hannah Webber; Nicolas Tardif; Gilberto S. Almeida; Rossitza Christova; Gunther Boysen; Mark W. Richards; Giuseppe Barone; Anthony Ford; Richard Bayliss; Paul A. Clarke; Johann de Bono; Nathanael S. Gray; Julian Blagg; Simon P. Robinson; Suzanne A. Eccles; Daniella Zheleva; James E. Bradner; Jan Molenaar; Igor Vivanco; Martin Eilers; Paul Workman; Charles Y. Lin; Louis Chesler

doi:10.1172/JCI134132

Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma

Evon Poon, Tong Liang, Yann Jamin, Susanne Walz, Colin Kwok, Anne Hakkert, Karen Barker, Zuzanna Urban, Khin Thway, Rhamy Zeid, Albert Hallsworth, Gary Box, Marli E. Ebus, Marco P. Licciardello, Yordan Sbirkov, Glori Lazaro, Elizabeth Calton, Barbara M. Costa, Melanie Valenti, Alexis de Haven BrandonHannah Webber, Nicolas Tardif, Gilberto S. Almeida, Rossitza Christova, Gunther Boysen, Mark W. Richards, Giuseppe Barone, Anthony Ford, Richard Bayliss, Paul A. Clarke, Johann de Bono, Nathanael S. Gray, Julian Blagg, Simon P. Robinson, Suzanne A. Eccles, Daniella Zheleva, James E. Bradner, Jan Molenaar, Igor Vivanco, Martin Eilers, Paul Workman, Charles Y. Lin, Louis Chesler

Group Molenaar

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › peer review

46 Citaten (Scopus)

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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.

Originele taal-2	Engels
Pagina's (van-tot)	5875-5892
Aantal pagina's	18
Tijdschrift	Journal of Clinical Investigation
Volume	130
Nummer van het tijdschrift	11
DOI's	https://doi.org/10.1172/JCI134132
Status	Gepubliceerd - 2 nov. 2020

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10.1172/JCI134132

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Poon, E., Liang, T., Jamin, Y., Walz, S., Kwok, C., Hakkert, A., Barker, K., Urban, Z., Thway, K., Zeid, R., Hallsworth, A., Box, G., Ebus, M. E., Licciardello, M. P., Sbirkov, Y., Lazaro, G., Calton, E., Costa, B. M., Valenti, M., ... Chesler, L. (2020). Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma. Journal of Clinical Investigation, 130(11), 5875-5892. https://doi.org/10.1172/JCI134132

@article{26fac0de0f394cca9eda58a6261730a2,

title = "Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma",

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.",

author = "Evon Poon and Tong Liang and Yann Jamin and Susanne Walz and Colin Kwok and Anne Hakkert and Karen Barker and Zuzanna Urban and Khin Thway and Rhamy Zeid and Albert Hallsworth and Gary Box and Ebus, {Marli E.} and Licciardello, {Marco P.} and Yordan Sbirkov and Glori Lazaro and Elizabeth Calton and Costa, {Barbara M.} and Melanie Valenti and {de Haven Brandon}, Alexis and Hannah Webber and Nicolas Tardif and Almeida, {Gilberto S.} and Rossitza Christova and Gunther Boysen and Richards, {Mark W.} and Giuseppe Barone and Anthony Ford and Richard Bayliss and Clarke, {Paul A.} and {de Bono}, Johann and Gray, {Nathanael S.} and Julian Blagg and Robinson, {Simon P.} and Eccles, {Suzanne A.} and Daniella Zheleva and Bradner, {James E.} and Jan Molenaar and Igor Vivanco and Martin Eilers and Paul Workman and Lin, {Charles Y.} and Louis Chesler",

note = "Publisher Copyright: Copyright: {\textcopyright} 2020 Poon et al.",

year = "2020",

month = nov,

day = "2",

doi = "10.1172/JCI134132",

language = "English",

volume = "130",

pages = "5875--5892",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "11",

}

Poon, E, Liang, T, Jamin, Y, Walz, S, Kwok, C, Hakkert, A, Barker, K, Urban, Z, Thway, K, Zeid, R, Hallsworth, A, Box, G, Ebus, ME, Licciardello, MP, Sbirkov, Y, Lazaro, G, Calton, E, Costa, BM, Valenti, M, de Haven Brandon, A, Webber, H, Tardif, N, Almeida, GS, Christova, R, Boysen, G, Richards, MW, Barone, G, Ford, A, Bayliss, R, Clarke, PA, de Bono, J, Gray, NS, Blagg, J, Robinson, SP, Eccles, SA, Zheleva, D, Bradner, JE, Molenaar, J, Vivanco, I, Eilers, M, Workman, P, Lin, CY & Chesler, L 2020, 'Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma', Journal of Clinical Investigation, vol. 130, nr. 11, blz. 5875-5892. https://doi.org/10.1172/JCI134132

TY - JOUR

T1 - Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma

AU - Poon, Evon

AU - Liang, Tong

AU - Jamin, Yann

AU - Walz, Susanne

AU - Kwok, Colin

AU - Hakkert, Anne

AU - Barker, Karen

AU - Urban, Zuzanna

AU - Thway, Khin

AU - Zeid, Rhamy

AU - Hallsworth, Albert

AU - Box, Gary

AU - Ebus, Marli E.

AU - Licciardello, Marco P.

AU - Sbirkov, Yordan

AU - Lazaro, Glori

AU - Calton, Elizabeth

AU - Costa, Barbara M.

AU - Valenti, Melanie

AU - de Haven Brandon, Alexis

AU - Webber, Hannah

AU - Tardif, Nicolas

AU - Almeida, Gilberto S.

AU - Christova, Rossitza

AU - Boysen, Gunther

AU - Richards, Mark W.

AU - Barone, Giuseppe

AU - Ford, Anthony

AU - Bayliss, Richard

AU - Clarke, Paul A.

AU - de Bono, Johann

AU - Gray, Nathanael S.

AU - Blagg, Julian

AU - Robinson, Simon P.

AU - Eccles, Suzanne A.

AU - Zheleva, Daniella

AU - Bradner, James E.

AU - Molenaar, Jan

AU - Vivanco, Igor

AU - Eilers, Martin

AU - Workman, Paul

AU - Lin, Charles Y.

AU - Chesler, Louis

PY - 2020/11/2

Y1 - 2020/11/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85094963402&partnerID=8YFLogxK

U2 - 10.1172/JCI134132

DO - 10.1172/JCI134132

M3 - Article

C2 - 33016930

AN - SCOPUS:85094963402

SN - 0021-9738

VL - 130

SP - 5875

EP - 5892

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 11

ER -

Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma

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