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 of Mybl2 using independent murine PCa cell lines representing phenotypic plasticity demonstrated Mybl2 loss 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 of Mybl2 and 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.
Cancer research communications. 2024 Aug 08 [Epub ahead of print]
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
Henry M. Jackson Foundation, Bethesda, United States., Yale New Haven Hospital, United States., Henry M. Jackson Foundation, Bethesda, MD, United States., Cedars-Sinai Medical Center, United States., University of California, Berkeley, El Cerrito, CA, United States., Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States., Dana-Farber Cancer Institute, United States., University of Minnesota, Minneapolis, United States., The University of Adelaide, Adelaide, SA, Australia., Dana-Farber Cancer Institute, Boston, MA, United States., University of Minnesota, Minnesota, MN, United States., Cedars-Sinai Medical Center, Los Angeles, CA, United States., Uniformed Services University of the Health Sciences, Bethesda, MD, United States.