dc.contributor.author | Poon, E | |
dc.contributor.author | Liang, T | |
dc.contributor.author | Jamin, Y | |
dc.contributor.author | Walz, S | |
dc.contributor.author | Kwok, C | |
dc.contributor.author | Hakkert, A | |
dc.contributor.author | Barker, K | |
dc.contributor.author | Urban, Z | |
dc.contributor.author | Thway, K | |
dc.contributor.author | Zeid, R | |
dc.contributor.author | Hallsworth, A | |
dc.contributor.author | Box, G | |
dc.contributor.author | Ebus, ME | |
dc.contributor.author | Licciardello, MP | |
dc.contributor.author | Sbirkov, Y | |
dc.contributor.author | Lazaro, G | |
dc.contributor.author | Calton, E | |
dc.contributor.author | Costa, BM | |
dc.contributor.author | Valenti, M | |
dc.contributor.author | De Haven Brandon, A | |
dc.contributor.author | Webber, H | |
dc.contributor.author | Tardif, N | |
dc.contributor.author | Almeida, GS | |
dc.contributor.author | Christova, R | |
dc.contributor.author | Boysen, G | |
dc.contributor.author | Richards, MW | |
dc.contributor.author | Barone, G | |
dc.contributor.author | Ford, A | |
dc.contributor.author | Bayliss, R | |
dc.contributor.author | Clarke, PA | |
dc.contributor.author | De Bono, J | |
dc.contributor.author | Gray, NS | |
dc.contributor.author | Blagg, J | |
dc.contributor.author | Robinson, SP | |
dc.contributor.author | Eccles, SA | |
dc.contributor.author | Zheleva, D | |
dc.contributor.author | Bradner, JE | |
dc.contributor.author | Molenaar, J | |
dc.contributor.author | Vivanco, I | |
dc.contributor.author | Eilers, M | |
dc.contributor.author | Workman, P | |
dc.contributor.author | Lin, CY | |
dc.contributor.author | Chesler, L | |
dc.date.accessioned | 2020-09-21T08:28:56Z | |
dc.date.issued | 2020-11-02 | |
dc.identifier.citation | The Journal of clinical investigation, 2020, 130 (11), pp. 5875 - 5892 | |
dc.identifier.issn | 0021-9738 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4072 | |
dc.identifier.eissn | 1558-8238 | |
dc.identifier.doi | 10.1172/jci134132 | |
dc.description.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. | |
dc.format | Print | |
dc.format.extent | 5875 - 5892 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER SOC CLINICAL INVESTIGATION INC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-07-29 | |
rioxxterms.versionofrecord | 10.1172/jci134132 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2020-11 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | The Journal of clinical investigation | |
pubs.issue | 11 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Molecular Addictions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Biology of Childhood Leukaemia | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Pre-Clinical MRI | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/16/17 Starting Cohort | |
pubs.publication-status | Published | |
pubs.volume | 130 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Cancer Pharmacology & Stress Response (CPSR) | |
icr.researchteam | Molecular Addictions | |
icr.researchteam | Prostate Cancer Targeted Therapy Group | |
icr.researchteam | Biology of Childhood Leukaemia | |
icr.researchteam | Paediatric Solid Tumour Biology and Therapeutics | |
icr.researchteam | Pre-Clinical MRI | |
dc.contributor.icrauthor | Poon, Evon | |
dc.contributor.icrauthor | Jamin, Yann | |
dc.contributor.icrauthor | Kwok, Colin | |
dc.contributor.icrauthor | Urban, Zuzanna | |
dc.contributor.icrauthor | Calton, Elizabeth Anne | |
dc.contributor.icrauthor | Valenti, Melanie | |
dc.contributor.icrauthor | Ford, Anthony | |
dc.contributor.icrauthor | Clarke, Paul | |
dc.contributor.icrauthor | De Bono, Johann | |
dc.contributor.icrauthor | Robinson, Simon | |
dc.contributor.icrauthor | Vivanco, Igor | |
dc.contributor.icrauthor | Workman, Paul | |
dc.contributor.icrauthor | Chesler, Louis | |