MYBL2 drives prostate cancer plasticity and identifies CDK2 as a therapeutic vulnerability in RB1-loss and neuroendocrine prostate cancer [ChIP-seq]. MYBL2 drives prostate cancer plasticity and identifies CDK2 as a therapeutic vulnerability in RB1-loss and neuroendocrine prostate cancer [ChIP-seq]

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. Overall design: To investigate the change in the regulatory landscape in phenotypic plasticity in prostate cancer we performed H3K27ac ChIPseq in Pten KO (SKO) and Pten:Rb1 KO (DKO) GEMMs.

表型可塑性（phenotypic plasticity）是驱动前列腺癌（prostate cancer, PCa）患者治疗抵抗的公认机制。尽管驱动表型可塑性的潜在分子病因已被探明，但目前仍未实现有效的治疗突破。为鉴定驱动前列腺癌表型可塑性的推定主调控转录因子（master regulator transcription factor, MR-TF），本研究采用多组学研究策略，结合前列腺癌基因工程小鼠模型（genetically engineered mouse models, GEMMs）与患者队列数据，将MYBL2鉴定为表现出表型可塑性的前列腺癌中显著富集的转录因子。使用代表表型可塑性的独立小鼠前列腺癌细胞系开展Mybl2遗传抑制实验，结果显示Mybl2缺失可显著削弱体内肿瘤生长能力与细胞适合度，并抑制多能性与干细胞特性相关的基因表达特征。由于目前尚无针对MYBL2的获批靶向药物，本研究借助MYBL2基因特征谱，鉴定出细胞周期蛋白依赖性激酶2（cyclin-dependent kinase-2, CDK2）作为潜在治疗靶点。CDK2抑制可模拟Mybl2遗传缺失的表型效应，并显著抑制体内肿瘤生长，同时伴随DNA损伤富集现象。综上，本研究证实MYBL2是驱动前列腺癌表型可塑性的关键主调控转录因子。此外，MYBL2高活性可作为筛选对CDK2抑制治疗敏感的前列腺癌患者的生物标志物。【整体实验设计】为探究前列腺癌表型可塑性的调控图谱变化，本研究在Pten单敲除（SKO）与Pten:Rb1双敲除（DKO）基因工程小鼠模型中开展了H3K27ac染色质免疫共沉淀测序（Chromatin Immunoprecipitation sequencing, ChIPseq）实验。