<i>MYBL2</i> mRNA expression as a potential biomarker of therapeutic response to genotoxic treatments in myelodysplastic syndrome

Bayley, Rachel; Blakemore, Daniel; García, Paloma

doi:10.18632/oncotarget.26477

Cited by 2 publications

(1 citation statement)

References 11 publications

(15 reference statements)

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“…Together, our study provides evidence that MYBL2 is an important MR-TF driving stemness in NEPC, and this increase in transcriptional function of MYBL2 highlights that NEPC would be susceptible to inhibition of CDK2. Previously, MYBL2 mRNA expression has been suggested as a biomarker to identify myelodysplastic syndrome patients that would respond to genotoxic treatments (67). These data raise rationale that CDK2 inhibition should be candidate target taken to clinical trial to test towards the treatment of NEPC patients.…”

Section: Discussionmentioning

confidence: 99%

MYBL2 drives prostate cancer plasticity and identifies CDK2 as a therapeutic vulnerability in RB1-loss and neuroendocrine prostate cancer

German,

Singh,

Fonseca

et al. 2024

Preprint

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Phenotypic plasticity is a recognized mechanism driving therapeutic resistance in prostate cancer (PCa) patients. While underlying molecular causations driving phenotypic plasticity have been identified, therapeutic success is yet to be achieved. To identify putative master regulator transcription factors (MR-TF) driving phenotypic plasticity in PCa, this work utilized a multiomic approach using genetically engineered mouse models of prostate cancer combined with patient data to identify MYBL2 as a significantly enriched transcription factor in PCa exhibiting phenotypic plasticity. Genetic inhibition ofMybl2using independent murine PCa cell lines representing phenotypic plasticity demonstratedMybl2loss significantly decreased in vivo growth as well as cell fitness and repressed gene expression signatures involved in pluripotency and stemness. Because MYBL2 is currently not druggable, a MYBL2 gene signature was employed to identify cyclin-dependent kinase-2 (CDK2) as a potential therapeutic target. CDK2 inhibition phenocopied genetic loss ofMybl2and significantly decreased in vivo tumor growth associated with enrichment of DNA damage. Together, this work demonstrates MYBL2 as an important MR-TF driving phenotypic plasticity in PCa. Further, high MYBL2 activity identifies PCa that would be responsive to CDK2 inhibition.SignificancePCa that escapes therapy targeting the androgen receptor signaling pathways via phenotypic plasticity are currently untreatable. Our study identifies MYBL2 as a MR-TF in phenotypic plastic PCa and implicates CDK2 inhibition as novel therapeutic target for this most lethal subtype of PCa.

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Section: Discussionmentioning

confidence: 99%