Loss of tristetraprolin activates NF-κB induced phenotypic plasticity and primes transition to lethal prostate cancer

Phenotypic plasticity is a hallmark of cancer and increasingly realized as a mechanism of resistance in prostate tumors progressing on second generation AR targeted therapy. With the advent of treating prostate cancer (PCa) patients upfront with these agents, it is critical to identify mechanisms and actionable targets that drive phenotypic plasticity and prevent emergence of resistance. Here, we report that loss of tristetraprolin (TTP, gene ZFP36), an RNA binding protein that regulates mRNA stability increases NF-κB activation and is associated with higher rates of aggressive disease and early recurrence in primary PCa. Given ZFP36 loss occurs in early PCa we also sought to examine the clinical and biological impact of ZFP36 loss combined with PTEN loss, a known driver of PCa. Analysis of independent primary PCa cohorts demonstrated that combined loss of PTEN and ZFP36 expression coincided with increased risk of recurrence. Engineering ZFP36 deletion specific to prostate luminal epithelial cells in vivo induced high-grade prostatic intraepithelial neoplasia (HG-PIN), and when combined with PTEN deletion resulted in rapid progression to invasive adenocarcinoma associated with increased proliferation and development of micro-metastases. Combined loss of ZFP36 and PTEN in mice significantly reduced overall survival as well as time to progression when mice were surgically castrated. Gene expression analysis revealed that loss of ZFP36 expression alters the cell state that is driven by PTEN loss, demonstrated by positive enrichment of gene sets including EMT, inflammation, TNFα/NF-κB, IL6-JAK/STAT3. In addition, our work revealed the unique finding that ZFP36 loss also induced enrichment of multiple gene sets involved in mononuclear cell migration, chemotaxis, and proliferation. Use of the NFκB inhibitor, dimethylaminoparthenolide (DMAPT) induced significant therapeutic responses in tumors with PTEN and ZFP36 co-loss and reversed resistance to castration. This work identifies a novel molecular mechanism which drives resistance to castration through loss of ZFP36 expression driving the induction of phenotypic plasticity, that can be reversed by inhibition of NF-κB activity using DMAPT.