We have reported that loss of tristetraprolin (TTP, gene name ZFP36), an RNA binding protein which modulates mRNA stability increases NF-kappa B activation and is associated with a higher rate of metastatic disease in prostatectomy series. Given TTP loss happens in early prostate cancer we sought to examine the clinical and biological impact when TTP loss occurs with PTEN loss which also occurs in early prostate cancer. Analysis of multiplex immunohistochemistry and gene expression profiling data of three different prostatectomy series all revealed an increased risk of relapse with loss of one of PTEN or TTP and even significantly higher risk of relapse with loss of both TTP and PTEN. We then engineered ZFP36 deletion in a previously characterized mouse model of prostate adenocarcinoma induced by PTEN deletion. Genetically engineered mouse models (GEMM) with ZFP36 +/- and -/- alone had minimal hyperplasia and PTEN-/- alone caused the expected prostatic intraepithelial neoplasia but PTEN -/- with ZFP36 +/- or -/- resulted in invasive cancer and development of micrometastases and shorter survivals without and with castration. Immunofluorescent IHC of the tumours revealed increased Ki-67 and phosph-p65 in the PTEN -/- with ZFP36 +/- or -/- versus PTEN -/- tumors. The NF-kappa B inhibitor, dimethylaminoparthenolide (DMAPT) resulted in significant cancer control at day 36 in PTEN/ZFP36 null allograft tumours. These findings were supported by cell death assays of organoid models. The hypersensitivity of PTEN/ZFP36 null cell line to DMAPT was seen with dose response curves with DMAPT LD50 being 4.52 uM PTEN -/-; 0.76 uM for PTEN -/- and TTP-/- and 8.66 uM for PTEN-/- and TTP-/- with silenced p65. In conclusion, loss of PTEN and TTP together results in prostate cancer that is clinically more aggressive than PTEN loss alone and this was corroborated by GEMM models. The latter revealed tumours with PTEN/TTP-null were more aggressive, minimally responsive to castration and had activation of NF-kappa B and hypersensitivity to DMAPT. This work supports clinical trials of DMAPT in castration resistant prostate cancer.