Abstract 5295: Combined loss of tristetraprolin (TTP) and PTEN leads to aggressive prostate cancer and hypersensitivity to nuclear factor kappa B (NFkB) inhibition

Abstract

Abstract We have reported that loss of tristetraprolin (TTP, gene name ZFP36), an RNA binding protein which modulates mRNA stability increased NFκB activation and is associated with higher rates of disease recurrence in prostatectomy series. Given TTP loss occurs in early prostate cancer we sought to examine the clinical and biological impact of TTP loss combined with PTEN loss, which also occurs in early prostate cancer. IHC revealed an increased risk of relapse with loss of one gene alone and a significantly higher risk of relapse with loss of both TTP and PTEN, (HR 4.50, p=0.04 on MVA adjusting for standard clinicopathologic factors). These findings were confirmed by analysis of RNA profiles of two publicly available prostatectomy series. Engineering ZFP36 deletion specific to prostate luminal cells in vivo induced high-grade prostatic intraepithelial neoplasia (HG-PIN), and when combined with PTEN deletion (P:Z) resulted in rapid progression to invasive adenocarcinoma associated with increased proliferation and development of micrometastases. Combined loss of PTEN and ZFP36 in mice significantly reduced overall survival (53.4 (P:Z+/-) and 49.6 (P:Z-/-) weeks versus 66.9 weeks in PTEN-/- (p<0.0001). Further, surgical castration of mice demonstrated that combined loss of ZFP36 and PTEN significantly accelerated progression to castration resistance versus PTEN alone (median survival, 56.1 (P:Z+/-) and 53.9 (P:Z-/-) weeks versus all PTEN-/- mice still alive by 70 weeks). Ex vivo analysis of organoid growth of the tumors revealed presence of budding with PTEN-/- with ZFP36-/- and almost none with PTEN-/-. These findings were recapitulated with GEMM-derived allograft tumor growth with tumor sizes 20 weeks after castration being 200mm3 in PTEN-/- versus 900mm3 with [PTEN-/- + TTP-/-] versus 600mm3 for PTEN-/- and 1200mm3 for [PTEN-/- + TTP-/-] after sham castration (all comparisons p < 0.05). When the PTEN/ZFP36 null allograft was treated with the NFκB inhibitor dimethylaminoparthenolide (DMAPT, D), tumor sizes 36 days after treatment were: vehicle - 2000mm3, castration (C) - 1500mm3; D alone - 600mm3; C + D - 500mm3 (all comparisons p<0.05; except D vs C + D; p=0.07). These findings were supported by cell death assays of organoid models for the GEMMs. The hypersensitivity of PTEN/ZFP36 null cell line to DMAPT was seen with dose response curves with DMAPT LD50 being 4.52 μM PTEN-/-; 0.76 μM [PTEN -/- + TTP-/-] and 8.66 μM for [PTEN-/- + TTP-/- + silenced p65]. In conclusion, combined loss of PTEN and TTP results in prostate cancer that is clinically more aggressive than PTEN loss alone and this was corroborated by GEMM models. Namely, PTEN/TTP null tumors were more aggressive, minimally responsive to castration, demonstrated activation of NFκB and hypersensitivity to DMAPT. This work supports the planned clinical trials of DMAPT in castration resistant prostate cancer Citation Format: Christopher J. Sweeney, Katherine Morel, Anis Hamid, Leigh Ellis. Combined loss of tristetraprolin (TTP) and PTEN leads to aggressive prostate cancer and hypersensitivity to nuclear factor kappa B (NFkB) inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5295.