Differential Effect of Non-Steroidal Anti-Inflammatory Drugs Aspirin and Naproxen against TMPRSS2-ERG (Fusion)-Driven and Non-Fusion-Driven Prostate Cancer

SIMPLE SUMMARY: Disparity in clinical outcome data due to the biological heterogeneity of prostate cancer (PCa) has drawn attention to approaches that stratify homogeneous subsets of patients. In recent years, PCa fusion genes (specifically TMPRSS2-ERG fusion) have been identified as oncogenic drivers with the potential for patient stratification and as targets for effective prevention/intervention strategies in drug efficacy trials. In the present study, employing relevant TMPRSS2-ERG (fusion)-driven and non-TMPRSS2-ERG-driven mouse models of PCa, we report the potential usefulness of the non-steroidal anti-inflammatory drugs (NSAIDs) aspirin and naproxen specifically against TMPSS2-ERG fusion-driven prostate tumorigenesis. These findings are consistent with the clinical observations and warrant further investigation of the molecular mechanisms and utility of NSAID interventions for precision cancer prevention. ABSTRACT: The consumption of the non-steroidal anti-inflammatory drug (NSAID) aspirin is associated with a significant reduction in the risk of developing TMPRSS2-ERG (fusion)-positive prostate cancer (PCa) compared to fusion-negative PCa in population-based case–control studies; however, no extensive preclinical studies have been conducted to investigate and confirm these protective benefits. Thus, the focus of this study was to determine the potential usefulness of aspirin and another NSAID, naproxen, in PCa prevention, employing preclinical models of both TMPRSS2-ERG (fusion)-driven (with conditional deletion of Pten) and non-TMPRSS2-ERG-driven (Hi-Myc(+/−) mice) PCa. Male mice (n = 25 mice/group) were fed aspirin- (700 and 1400 ppm) and naproxen- (200 and 400 ppm) supplemented diets from (a) 6 weeks until 32 weeks of Hi-Myc(+/−) mice age; and (b) 1 week until 20 weeks post-Cre induction in the fusion model. In all NSAID-fed groups, compared to no-drug controls, there was a significant decrease in higher-grade adenocarcinoma incidence in the TMPRSS2-ERG (fusion)-driven PCa model. Notably, there were no moderately differentiated (MD) adenocarcinomas in the dorsolateral prostate of naproxen groups, and its incidence also decreased by ~79–91% in the aspirin cohorts. In contrast, NSAIDs showed little protective effect against prostate tumorigenesis in Hi-Myc(+/−) mice, suggesting that NSAIDs exert a specific protective effect against TMPRSS2-ERG (fusion)-driven PCa.