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.
Highlights
The prominent role of Myc family protooncogene transcription factors (TFs) (MYC, MYCN, MYCL) in the genesis of adult and childhood cancers makes these TFs attractive targets for drug discovery and development [1]
We show that the developmental clinical drug CYC065 — a potent and selective CDK9/2 inhibitor with enhanced pharmacokinetic and pharmacodynamics properties — is highly effective against NB
We demonstrate mechanistically that CYC065’s effects against highrisk MYCN-driven NB are a result of CDK9 inhibition resulting in selective loss of MYCN nascent transcription, which in turn leads to cell growth arrest and, in addition, sensitizes NB cells to apoptosis upon concomitant inhibition of CDK2 by the drug
Summary
The prominent role of Myc family protooncogene transcription factors (TFs) (MYC, MYCN, MYCL) in the genesis of adult and childhood cancers makes these TFs attractive targets for drug discovery and development [1]. Across MYCN phosphorylation-deficient mutant variants, MYCN binding at promoters and enhancers was unchanged upon CYC065 treatment (Supplemental Figure 7, A and B), with the exception of the T58A S62A double mutant, which exhibited a global decrease in MYCN occupancy (Supplemental Figure 7, C and D) These data are consistent with our prior conclusions that CYC065 selectively targets nascent MYCN transcription in the context of endogenous MYCN amplification. In the TH-ALKF1174L/TH-MYCN genetically engineered mouse model (which expresses very high levels of murine Mycn as a consequence of direct activity of ALK on the endogenous Mycn promoter) [37], we observed tumor regression and a dramatic increase in overall survival compared with that seen with vehicle control (Figure 6D) These effects occurred at welltolerated doses of CYC065 (Supplemental Figure 8D), suggesting a clear therapeutic index for CYC065 in the most highly aggressive MYCN-deregulated forms of NB. In other cancer models with Myc deregulated and nonderegulated subtypes, we observed similar trends, with selective inhibition of Myc-deregulated tumors coinciding with loss of Myc (Supplemental Figure 8J)
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