Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma.
Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma.
复制标题
DOI：
10.1172/jci134132
复制
发表时间：
2020-11-02
期刊：
影响因子：
--
通讯作者：
Chesler L
中科院分区：
文献类型：
--
作者：
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
致癌Myc转录因子的不可治疗性对神经母细胞瘤的治疗提出了挑战，神经母细胞瘤是一种儿科癌症，其中MYCN扩增与不利的结果密切相关。在这里，我们发现CYC 065（fadraciclib），一种CDK 9和CDK 2的临床抑制剂，通过多种机制选择性靶向MYCN扩增的神经母细胞瘤。CDK 9-转录延伸复合物P-TEFb的组分-与MYCN-扩增子超增强剂结合，并且其抑制导致新生MYCN转录的选择性丧失。MYCN损失导致生长停滞，使细胞在CDK 2抑制后对凋亡敏感。在MYCN扩增的神经母细胞瘤中，MYCN侵入活性增强子，驱动转录编码的肾上腺素能基因表达程序，该程序被CYC 065选择性逆转。间充质神经母细胞瘤中MYCN过表达足以诱导肾上腺素能特性并使细胞对CYC 065敏感。CYC 065与替莫唑胺（一种复发性神经母细胞瘤的参考疗法）一起使用，在体内引起神经母细胞瘤生长的长期抑制，突出了CDK 9/2抑制在治疗MYCN扩增的神经母细胞瘤中的临床潜力。
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.