Biobank of genetically defined murine prostate cancer tumoroids uncovers oncogenic pathways and drug vulnerabilities driven by PTEN-loss

Prostate cancer (PCa) is the second most common cancer in men and shows high inter- and intra-patient heterogeneity. Consequently, treatment options are limited and there is a lack of representative preclinical models. Here we establish a comprehensive biobank of murine organoids and tumoroids that reflect common patient mutations. We demonstrate that the deletion of Pten alone, or in combination with Stat3 , or Tp53 , drives the activation of cancer-related pathways in both prostate organoids and tumour-derived tumoroids. A medium-throughput drug screen identified two potent compounds, the PDPK1/AKT/FLT dual pathway inhibitor and the sirtuin inhibitor tenovin-6, which effectively suppressed tumoroid proliferation. Notably, these compounds also inhibited the growth of several human PCa cell lines and displayed synergistic effects when combined with the standard-of-care antiandrogen enzalutamide. Together, our findings provide evidence that murine tumoroids are versatile preclinical models for studying PCa tumorigenesis and drug sensitivities to develop novel therapeutic options for PCa patients.