Abstract 4749: Evaluating NUAK2 as a potential target in neuroendocrine prostate cancer

Abstract Background: Neuroendocrine Prostate Cancer (NEPC) is an aggressive and lethal prostate cancer subtype. Due to Androgen Receptor-independence, NEPC lacks targeted therapeutics, with platinum-based chemotherapy serving as the primary treatment modality. This highlights the need for new molecular targets in NEPC. NUAK2, also known as sucrose non-fermenting (SNF1)-like AMPK-related kinase (SNARK) is an unstudied kinase. Yet, pan-cancer analysis shows increased expression of NUAK2 across several malignancies. Analysis of prostate cancer and NEPC datasets revealed a significant increase in NUAK2 expression levels correlating with disease progression. The objective of our study was to determine if NUAK2 is essential for NEPC tumor growth. Methods: To investigate the therapeutic potential of NUAK2 in NEPC, we conducted genetic and pharmacological modulation of NUAK2 both in vitro and in vivo. We conducted label-free quantitative phospho-proteomic and proximity ligation interactome analyses of NUAK2 using LC-MS/MS to elucidate its role in NEPC. Results: NUAK2 knockdown significantly decreased proliferation and 3D spheroid growth in NEPC preclinical models. CRISPR-Cas9-mediated knockout of NUAK2 in NCI-H600 cells led to reduced tumor growth in vivo. Furthermore, NUAK2 overexpression accelerated NEPC growth in a kinase-dependent manner. Pharmacological inhibition of NUAK2 significantly reduced the growth of NEPC cell-line and patient-derived xenografts. Phosphoproteome and interactome studies by LC-MS/MS and pathway enrichment analysis revealed the role of NUAK2 in chromatin remodeling, mRNA metabolic processes, and cytoskeleton organization. Conclusions: Collectively, our study highlights NUAK2 is essential for NEPC tumor growth and is an actionable target in NEPC. Citation Format: Umar Mehraj, Shaista Manzoor, Julie Parks, Emily Cordova, Everardo Macias. Evaluating NUAK2 as a potential target in neuroendocrine prostate cancer [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 4749.