Biobank of genetically defined murine prostate cancer tumoroids uncovers oncogenic pathways and drug vulnerabilities driven by PTEN-loss
Kalla, J.; Dillinger, T.; Pavlovicova, Z.; Jacob, R.; Atas, E.; Baskan, A.; Draganic, K.; Tiefenbacher, A.; Limberger, T.; Mair, T.; Wasinger, G.; Villanti, L.; Kubicek, S.; Kenner, L.; Egger, G.
Show abstract
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.
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