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

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.

Molecular Mechanisms of MYCN Dysregulation in Cancers

“…A covalent inhibitor of CDK7, THZ1, selectively targets MYCN -amplified neuroblastoma cells, leading to global suppression of MYCN -dependent transcriptional amplification and sustained growth inhibition of tumors in a mouse model of neuroblastoma ( 85 ). CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2 (a major regulator of apoptotic cell death), selectively targets MYCN -amplified neuroblastoma through a loss of MYCN transcription and growth arrest, followed by sensitizing cells for apoptosis as a result of CDK2 inhibition ( 86 ). Furthermore, the combined use of CYC065 with temozolomide (a reference therapy for relapsed neuroblastoma), leads to long-term repression of neuroblastoma growth in vivo ( 86 ).…”

“…CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2 (a major regulator of apoptotic cell death), selectively targets MYCN -amplified neuroblastoma through a loss of MYCN transcription and growth arrest, followed by sensitizing cells for apoptosis as a result of CDK2 inhibition ( 86 ). Furthermore, the combined use of CYC065 with temozolomide (a reference therapy for relapsed neuroblastoma), leads to long-term repression of neuroblastoma growth in vivo ( 86 ).…”

Biological Role of MYCN in Medulloblastoma: Novel Therapeutic Opportunities and Challenges Ahead

“…Cyclin dependent kinases such as CDK7 and CDK9 play a key role in regulating transcriptional activity of MYCN (141)(142)(143).…”

“…Cyclin dependent kinases such as CDK7 and CDK9 play a key role in regulating transcriptional activity of MYCN ( 141 – 143 ). We have identified strong enrichment for CDK9 at both the MYCN promoter and the distal super enhancer and shown that pharmacologic blockade of CDK9 using Fadraciclib targeted MYCN-dependent transcriptional landscape ( 143 ).…”

Targeting MYCN in Pediatric and Adult Cancers

“…Indeed, THZ1, a covalent inhibitor of CDK7, was found to selectively target MYCN -amplified NB cells, leading to global repression of MYCN -dependent transcriptional amplification and reductions in expression of SE-associated oncogenic drivers including MYCN itself and suppression of NB tumor xenograft growth ( 87 ). CYC065, an inhibitor of CDK9 and CDK2, was found to selectively target MYCN-amplified NB cells by leading to a selective loss of nascent MYCN transcription ( 105 ). These studies indicate that the inhibition of CDK7 or CDK9 can be exploited to disrupt aberrant MYCN -driven transcription and to repress MYCN gene transcription as a therapeutic for MYCN -driven cancers ( Figure 2 ).…”