NUAK1 governs centrosome replication in pancreatic cancer via MYPT1/PP1β and GSK3β-dependent regulation of PLK4

Whyte, D. et al. (2023) NUAK1 governs centrosome replication in pancreatic cancer via MYPT1/PP1β and GSK3β-dependent regulation of PLK4. Molecular Oncology, 17(7), pp. 1212-1227. (doi: 10.1002/1878-0261.13425) (PMID:36975767) (PMCID:PMC10323901)

Abstract

The AMP-activated protein kinase (AMPK)-related kinase NUAK1 (NUAK family SNF1-like kinase 1) has emerged as a potential vulnerability in MYC-dependent cancer but the biological roles of NUAK1 in different settings are poorly characterised, and the spectrum of cancer types that exhibit a requirement for NUAK1 is unknown. Unlike canonical oncogenes, NUAK1 is rarely mutated in cancer and appears to function as an obligate facilitator rather than a cancer driver per se. Although numerous groups have developed small-molecule NUAK inhibitors, the circumstances that would trigger their use and the unwanted toxicities that may arise as a consequence of on-target activity are thus undetermined. Reasoning that MYC is a key effector of RAS pathway signalling and the GTPase KRAS is almost uniformly mutated in pancreatic ductal adenocarcinoma (PDAC), we investigated whether this cancer type exhibits a functional requirement for NUAK1. Here, we show that high NUAK1 expression is associated with reduced overall survival in PDAC and that inhibition or depletion of NUAK1 suppresses growth of PDAC cells in culture. We identify a previously unknown role for NUAK1 in regulating accurate centrosome duplication and show that loss of NUAK1 triggers genomic instability. The latter activity is conserved in primary fibroblasts, raising the possibility of undesirable genotoxic effects of NUAK1 inhibition.

• Item Type: Articles
• Additional Information: Funding for this work was provided by a Pancreatic Cancer UK Future Leaders Academy to JM and DJM, supporting DW; Worldwide Cancer project grant AICR 15-0279 to DJM and JM, supporting NM; and Cancer Research UK (CRUK) Core Institute grants A17196 and A31287. JM was supported by CRUK grant A29996; MB was supported by CRUK grant A29252; GS was supported by Merck/Cancer Research Horizons project agreement U14111.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Nixon, Mr Colin and Paul, Dr Nikki and Walsh, Peter and Wilczynska, Dr Ania and Murphy, Professor Daniel and Morton, Professor Jen and Whyte, Declan and Bushell, Professor Martin and Skalka, Dr George
• Authors: Whyte, D., Skalka, G., Walsh, P., Wilczynska, A., Paul, N. R., Mitchel, C., Nixon, C., Clarke, W., Bushell, M., Morton, J. P., Murphy, D. J., and Muthalagu, N.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Molecular Oncology
• Publisher: Wiley
• ISSN: 1574-7891
• ISSN (Online): 1878-0261
• Published Online: 28 March 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Molecular Oncology 17(7):1212-1227
• Publisher Policy: Reproduced under a Creative Commons License