Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma.
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Authors
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
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
Document Type
Journal Article
Date
2020-11-02
Date Accepted
2020-07-29
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.
Citation
The Journal of clinical investigation, 2020, 130 (11), pp. 5875 - 5892
Source Title
Publisher
AMER SOC CLINICAL INVESTIGATION INC
ISSN
0021-9738
eISSN
1558-8238
Research Team
Cancer Pharmacology & Stress Response (CPSR)
Molecular Addictions
Prostate Cancer Targeted Therapy Group
Biology of Childhood Leukaemia
Paediatric Solid Tumour Biology and Therapeutics
Pre-Clinical MRI
Molecular Addictions
Prostate Cancer Targeted Therapy Group
Biology of Childhood Leukaemia
Paediatric Solid Tumour Biology and Therapeutics
Pre-Clinical MRI