ROLE OF POST-TRANSLATIONAL MODIFICATIONS IN TREATMENT-INDUCED NEUROENDOCRINE PROSTATE CANCER

This dissertation examines the molecular mechanisms underlying treatment-induced neuroendocrine prostate cancer (NEPC), a highly aggressive and therapy-resistant subtype of prostate cancer. Focusing on stress response pathways and lineage plasticity, this work identifies the roles of UCHL1, HSC70, and PRMT5 in driving neuroendocrine differentiation following androgen receptor pathway inhibition. Using a combination of genetically engineered mouse models, human-derived xenografts, and prostate cancer cell lines, I demonstrate how these factors contribute to treatment resistance and tumor evolution. Additionally, this work explores the therapeutic potential of PRMT5 and UCHL1 inhibition and introduces a novel conceptual framework involving tumor clonal competition as a strategy to suppress aggressive phenotypes. These findings provide mechanistic insights into NEPC progression and highlight potential avenues for therapeutic intervention.