Abstract 3065: Tribbles 2 drives lineage maintenance and survival in neuroendocrine prostate cancer by regulating N-Myc stability

Abstract Neuroendocrine prostate cancer (NEPC) is a highly aggressive and treatment-resistant subtype of prostate cancer, characterized by an increased propensity for visceral metastasis. As prostate cancer develops resistance to second-generation androgen receptor inhibitors, such as enzalutamide, many patients exhibit tumors with highly proliferative, metastatic cells that adopt neuroendocrine features. This form of treatment-emergent NEPC (t-NEPC) occurs in over 20% of cases, contrasting with the much rarer de novo NEPC, where neuroendocrine (NE) cells (∼1%) within the prostate transform into malignant entities. The clinical management of NEPC is challenging due to a limited understanding of molecular targets that can selectively combat these rapidly growing and invasive cells. One intriguing target is the pseudokinase Tribbles 2 (TRIB2), which has been found to be overexpressed in both t-NEPC and de novo NEPC. Elevated TRIB2 expression is implicated in promoting neuroendocrine differentiation in prostate adenocarcinoma cells, facilitating their escape from androgen-dependence and contributing to resistance against AR inhibitors. Functionally, TRIB2 enhances tumor cell survival and proliferation by fostering the adoption of neuroendocrine traits, thereby accelerating disease progression. Inhibition of TRIB2, however, reverses neuroendocrine traits and restores sensitivity to anti-androgen therapies, indicating that TRIB2 plays a critical role in therapeutic resistance by driving cellular trans-differentiation. Despite this, the precise mechanisms by which TRIB2 contributes to the onset and maintenance of neuroendocrine features in prostate cancer remain unclear. Our studies using well-characterized NEPC tumors, and established NEPC cell lines have consistently shown that TRIB2 is closely associated with neuroendocrine phenotypes both in vitro and in vivo. Notably, TRIB2 appears to regulate these features by promoting the upregulation and stabilization of N-Myc, a key oncogene in neuroendocrine differentiation, through inhibition of its ubiquitination mediated proteasomal degradation. CRISPR-Cas9 mediated modulation of TRIB2 expression levels in NEPC cells and tumors results in corresponding changes in their neuroendocrine characteristics, reinforcing the notion that TRIB2 is a critical driver of NE trans-differentiation. These findings highlight TRIB2 as a novel regulator in the progression and maintenance of NEPC, with its effects likely mediated through downstream modulation of N-Myc activity. Citation Format: Jitender Monga, Rohith Guddeti, Craig Rogers, Shirish Gadgeel, Dhananjay Chitale, Jagadananda Ghosh. Tribbles 2 drives lineage maintenance and survival in neuroendocrine prostate cancer by regulating N-Myc stability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3065.