Division of Clinical Studies and.
Division of Cancer Therapeutics, Institute of Cancer Research (ICR), London and Royal Marsden NHS Trust, Sutton, United Kingdom.
J Clin Invest. 2020 Nov 2;130(11):5875-5892. doi: 10.1172/JCI134132.
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.
致癌转录因子 Myc 的不可成药性给神经母细胞瘤的治疗带来了挑战，这种儿科癌症中 MYCN 扩增与不良预后密切相关。在这里，我们表明，CYC065（法德西立克），一种 CDK9 和 CDK2 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。CDK9 - 转录延伸复合物 P-TEFb 的一个组成部分 - 与 MYCN 扩增子超级增强子结合，其抑制导致新生 MYCN 转录的选择性丢失。MYCN 的丢失导致细胞生长停滞，并在 CDK2 抑制后使细胞对细胞凋亡敏感。在 MYCN 扩增的神经母细胞瘤中，MYCN 侵入活跃的增强子，驱动转录编码的肾上腺素能基因表达程序，该程序可被 CYC065 选择性逆转。间充质神经母细胞瘤中 MYCN 的过表达足以诱导肾上腺素能特性，并使细胞对 CYC065 敏感。与替莫唑胺（用于复发性神经母细胞瘤的参考疗法）联合使用 CYC065 可在体内长期抑制神经母细胞瘤的生长，突出了 CDK9/2 抑制在治疗 MYCN 扩增的神经母细胞瘤中的临床潜力。
