4.8 Article

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

期刊

JOURNAL OF CLINICAL INVESTIGATION
卷 130, 期 11, 页码 5875-5892

出版社

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI134132

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资金

  1. Cancer Research UK (CRUK) [C34648/A18339, C34648/A28278]
  2. Children with Cancer UK [2014/174, 2016/233]
  3. Christophers Smile [CSM001X]
  4. INSTINCT
  5. SPARKS [12RMH01]
  6. Neuroblastoma Society
  7. EU [EU-116064-1]
  8. ICR
  9. CRUK
  10. EPSRC Cancer Imaging Centre [C1060/A10334]
  11. ICR CRUK Imaging Centre [C1090/A16464]
  12. Wellcome Trust [091763Z/10/Z]
  13. NIH
  14. NCI [1R01CA215452-01]
  15. German Federal Ministry of Education and Research (BMBF) as part of the SYSMED-NB consortium
  16. CRUK [C309/A11566, C24461/A23302]
  17. ICR London
  18. Cyclacel Ltd.
  19. MRC
  20. Department of Health (England)
  21. MRC [MC_PC_18051, MC_PC_16047] Funding Source: UKRI

向作者/读者索取更多资源

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. COK9 - 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.

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