Insight

Photo taken from EllisLab/X

Aug 17, 2024, 10:28

MYBL2 Drives Prostate Cancer Plasticity

Ellis Lab shared on X:

“What to go over a smaller paper just out from the lab in Cancer Research Communications.

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

Authors: Beatriz German, Sarah A. Alaiwi, Kun-Lin Ho, Jagpreet S. Nanda, Marcos A. S. Fonseca, Deborah L Burkhart, Anjali V. Sheahan, Hannah E. Bergom, Katherine L. Morel, Himisha Beltran, Justin H. Hwang, Matthew L. Freedman, Kate Lawrenson, Leigh Ellis

Thanks to all involved and to first author Beatriz German for bringing this home.

Some major points below:

Chromatin remodeling is a well accepted mechanism driving Phenotypic Plasticity (NEPC) in Prostate Cancer therapies needed Integrating H3K27ac/ATACseq we defined a landscape of MR-TFs enriched in a GEMM with concurrent Pten:Rb1 KO. Analysis had us interested in MYB (sp: MYBL2).

We demonstrated that MYBL2 was enriched in CRPC-Ad – but most enriched in NEPC patients. Different plasticity gene sig also positively correlated with a MYBL2 gene sig.

MYBL2 is the most significant genetic dependency within the MYB family of TFs in PCa, and MYBL2 drives Anchorage independent growth and DNA synthesis (known).

Using RNAseq we further validated Fig 3 results showing MYBL2 KO resulted in loss of multiple gene sets associated with stemess and pluripotency. High expression of MYBL2 in human Adeno primary and CRPC PCa samples demonstrate increased stemness.

MYBL2 KO in vivo perturbs tumor growth – drug target? not right but maybe in the near future? To translate our ‘MYBL2 knowledge’ towards a therapy target we used a MYBL2 gene signature to nominate targets. We focused on CDK2-novel and enriched in NEPC.

Using a CDK2 degrader to treat mice bearing 2 independent murine ‘NEPC’ tumor models, we demonstrate CDK2 strong anti-tumor activity decreasing proliferation and increasing DNA damage in both tumor genotypes.

Again just want to thank all those involved (see authorship). It takes a village – even for the smaller papers.”

Source: Ellis Lab/X

Anjali V. Sheahan Beatriz German cancer Cancer Research Communications Deborah L Burkhart Ellis Lab Hannah E. Bergom Himisha Beltran Jagpreet S. Nanda Justin H. Hwang Kate Lawrenson Katherine L. Morel Kun-Lin Ho Leigh Ellis Marcos A. S. Fonseca Matthew L. Freedman MYBL2 OncoDaily Oncology prostate cancer Research Communications Sarah A. Alaiwi

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