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Updated: Dec 6, 2025

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

Evon Poon1,2, Tong Liang3, Yann Jamin4

  • 1Division of Clinical Studies and.

The Journal of Clinical Investigation
|October 5, 2020
PubMed

Insights

CYC065 selectively targets MYCN-amplified neuroblastoma by inhibiting CDK9 and CDK2. This drug reduces MYCN transcription, induces apoptosis, and reverses adrenergic gene expression, offering a promising therapy for this pediatric cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pediatric Cancer Research

Background:

  • MYCN amplification in neuroblastoma is linked to poor prognosis.
  • Oncogenic Myc transcription factors are challenging therapeutic targets.

Purpose of the Study:

  • To investigate the efficacy of CYC065 (fadraciclib), a CDK9 and CDK2 inhibitor, against MYCN-amplified neuroblastoma.
  • To elucidate the mechanisms by which CYC065 targets neuroblastoma cells.

Main Methods:

  • Assessing CYC065's effect on MYCN transcription and neuroblastoma cell viability.
  • Investigating the role of CDK9 in MYCN superenhancer binding and transcription.
  • Evaluating the impact of CYC065 on MYCN-driven gene expression programs.
  • Testing combination therapy with temozolomide in vivo.

Main Results:

  • CYC065 selectively inhibited MYCN transcription by targeting CDK9 at the MYCN-amplicon superenhancer.
  • MYCN loss sensitized neuroblastoma cells to apoptosis upon CDK2 inhibition.
  • CYC065 reversed MYCN-driven adrenergic gene expression in neuroblastoma.
  • Combination therapy with temozolomide suppressed tumor growth in vivo.

Conclusions:

  • CYC065 demonstrates significant therapeutic potential for MYCN-amplified neuroblastoma.
  • Targeting CDK9/2 offers a selective approach to treating this aggressive pediatric cancer.
  • CYC065's ability to reverse MYCN-driven gene expression is a key mechanism of action.
Keywords:
CancerOncologyTranscriptionTranslation

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