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MYBL2 Drives Prostate Cancer Plasticity: Inhibiting Its Transcriptional Target CDK2 for RB1-Deficient Neuroendocrine

Beatriz German1,2,3,4, Sarah A Alaiwi5, Kun-Lin Ho1,2,3

  • 1Department of Surgery, Center for Prostate Disease Research, Murtha Cancer Center Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland.

Cancer Research Communications
|August 8, 2024
PubMed

Insights

We identified MYBL2 as a key driver of treatment-resistant prostate cancer. Inhibiting CDK2, a target linked to MYBL2, shows promise for treating this aggressive cancer subtype.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Phenotypic plasticity contributes to therapeutic resistance in prostate cancer.
  • Existing treatments struggle against prostate cancers that develop resistance via plasticity.

Purpose of the Study:

  • Identify master regulator transcription factors (MR-TFs) driving phenotypic plasticity in prostate cancer.
  • Determine if targeting identified factors or related pathways can overcome resistance.

Main Methods:

  • Utilized a multiomic approach with genetically engineered mouse models and patient data.
  • Performed genetic inhibition of MYBL2 in prostate cancer cell lines.
  • Employed a MYBL2 gene signature to identify therapeutic targets.
  • Investigated CDK2 inhibition as a therapeutic strategy.

Main Results:

  • Identified MYBL2 as a significantly enriched MR-TF in phenotypically plastic prostate cancer.
  • Genetic inhibition of MYBL2 reduced tumor growth, cell fitness, and stemness signatures.
  • CDK2 inhibition mimicked MYBL2 loss, decreasing tumor growth and inducing DNA damage.
  • High MYBL2 activity predicts response to CDK2 inhibition.

Conclusions:

  • MYBL2 is a critical MR-TF driving phenotypic plasticity and therapeutic resistance in prostate cancer.
  • CDK2 inhibition represents a novel therapeutic strategy for MYBL2-driven, treatment-resistant prostate cancer.

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