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Fu W, Zhao MT, Driver LM, et al. NUAK family kinase 2 is a novel therapeutic target for prostate cancer. Mol Carcinog. 2021;doi: 10.1002/mc.23374.
Fu, W., Zhao, M. T., Driver, L. M., Schirmer, A. U., Yin, Q., You, S., Freedland, S. J., DiGiovanni, J., Drewry, D. H., & Macias, E. (2021). NUAK family kinase 2 is a novel therapeutic target for prostate cancer. Molecular carcinogenesis, . https://doi.org/10.1002/mc.23374
Fu, Weiwei, et al. "NUAK family kinase 2 is a novel therapeutic target for prostate cancer." Molecular carcinogenesis vol. (2021). doi: https://doi.org/10.1002/mc.23374
Fu W, Zhao MT, Driver LM, Schirmer AU, Yin Q, You S, Freedland SJ, DiGiovanni J, Drewry DH, Macias E. NUAK family kinase 2 is a novel therapeutic target for prostate cancer. Mol Carcinog. 2021 Nov 24; doi: 10.1002/mc.23374. Epub 2021 Nov 24. PMID: 34818445.
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Mol Carcinog. 2021 Nov 24; doi: 10.1002/mc.23374. Epub 2021 Nov 24.

NUAK family kinase 2 is a novel therapeutic target for prostate cancer.

Molecular carcinogenesis

Weiwei Fu, Megan T Zhao, Lucy M Driver, Amelia U Schirmer, Qi Yin, Sungyong You, Stephen J Freedland, John DiGiovanni, David H Drewry, Everardo Macias

Affiliations

  1. Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China.
  2. Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA.
  3. Department of Biomedical Science, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  4. Department of Surgery and Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  5. Durham VA Medical Center, Durham, North Carolina, USA.
  6. Division of Pharmacology and Toxicology and Dell Pediatric Research Institute, The University of Texas at Austin, Austin, Texas, USA.
  7. Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  8. UNC Lineberger Comprehensive Cancer Center, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

PMID: 34818445 DOI: 10.1002/mc.23374

Abstract

Current advancements in prostate cancer (PC) therapies have been successful in slowing PC progression and increasing life expectancy; however, there is still no curative treatment for advanced metastatic castration resistant PC (mCRPC). Most treatment options target the androgen receptor, to which many PCs eventually develop resistance. Thus, there is a dire need to identify and validate new molecular targets for treating PC. We found NUAK family kinase 2 (NUAK2) expression is elevated in PC and mCRPC versus normal tissue, and expression correlates with an increased risk of metastasis. Given this observation and because NUAK2, as a kinase, is actionable, we evaluated the potential of NUAK2 as a molecular target for PC. NUAK2 is a stress response kinase that also plays a role in activation of the YAP cotranscriptional oncogene. Combining pharmacological and genetic methods for modulating NUAK2, we found that targeting NUAK2 in vitro leads to reduction in proliferation, three-dimensional tumor spheroid growth, and matrigel invasion of PC cells. Differential gene expression analysis of PC cells treated NUAK2 small molecule inhibitor HTH-02-006 demonstrated that NUAK2 inhibition results in downregulation of E2F, EMT, and MYC hallmark gene sets after NUAK2 inhibition. In a syngeneic allograft model and in radical prostatectomy patient derived explants, NUAK2 inhibition slowed tumor growth and proliferation rates. Mechanistically, HTH-02-006 treatment led to inactivation of YAP and the downregulation of NUAK2 and MYC protein levels. Our results suggest that NUAK2 represents a novel actionable molecular target for PC that warrants further exploration.

© 2021 Wiley Periodicals LLC.

Keywords: NUAK2; kinase inhibitor; patient derived explants; prostate cancer

References

  1. U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visualizations Tool, based on 2019 submission data (1999-2017). 2020. - PubMed
  2. Sun X, Gao L, Chien HY, Li WC, Zhao J. The regulation and function of the NUAK family. J Mol Endocrinol. 2013;51:R15-R22. - PubMed
  3. Nguyen DT, Mathias S, Bologa C, et al. Pharos: collating protein information to shed light on the druggable genome. Nucleic Acids Res. 2017;45:D995-D1002. - PubMed
  4. Rodgers G, Austin C, Anderson J, et al. Glimmers in illuminating the druggable genome. Nat Rev Drug Discovery. 2018;17:301-302. - PubMed
  5. Roskoski R Jr. Properties of FDA-approved small molecule protein kinase inhibitors: a 2021 update. Pharmacol Res. 2021;165:105463 - PubMed
  6. Humbert N, Navaratnam N, Augert A, et al. Regulation of ploidy and senescence by the AMPK-related kinase NUAK1. EMBO J. 2010;29:376-386. - PubMed
  7. Yuan WC, Pepe-Mooney B, Galli GG, et al. NUAK2 is a critical YAP target in liver cancer. Nat Commun. 2018;9:4834. - PubMed
  8. Gill MK, Christova T, Zhang YY, et al. A feed forward loop enforces YAP/TAZ signaling during tumorigenesis. Nat Commun. 2018;9:3510. - PubMed
  9. Zheng Y, Pan D. The Hippo signaling pathway in development and disease. Dev Cell. 2019;50:264-282. - PubMed
  10. Yamamoto H, Takashima S, Shintani Y, et al. Identification of a novel substrate for TNFalpha-induced kinase NUAK2. Biochem Biophys Res Commun. 2008;365:541-547. - PubMed
  11. Yamamoto H, Takashima S, Shintani Y, et al. Identification of a novel substrate for TNFα-induced kinase NUAK2. Biochem Biophys Res Commun. 2008;365:541-547. - PubMed
  12. Faisal M, Kim JH, Yoo KH, Roh EJ, Hong SS, Lee SH. Development and therapeutic potential of NUAKs inhibitors. J Med Chem. 2021;64:2-25. - PubMed
  13. Namiki T, Yaguchi T, Nakamura K, et al. NUAK2 amplification coupled with PTEN deficiency promotes melanoma development via CDK activation. Cancer Res. 2015;75:2708-2715. - PubMed
  14. Zanconato F, Cordenonsi M, Piccolo S. YAP/TAZ at the roots of cancer. Cancer Cell. 2016;29:783-803. - PubMed
  15. Salem O, Hansen CG. The Hippo pathway in prostate. Cancer Cells. 2019;8(4):370. - PubMed
  16. Schirmer AU, Driver LM, Zhao MT, et al. Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer. Mol Ther. 2021. doi:10.1016/j.ymthe.2021.08.029 - PubMed
  17. Dambal S, Alfaqih M, Sanders S, et al. 27-Hydroxycholesterol impairs plasma membrane lipid raft signaling as evidenced by inhibition of IL6-JAK-STAT3 signaling in prostate cancer cells. Mol Cancer Res. 2020;18:671-684. - PubMed
  18. Saha A, Blando J, Fernandez I, Kiguchi K, DiGiovanni J. Linneg Sca-1high CD49f high prostate cancer cells derived from the Hi-Myc mouse model are tumor-initiating cells with basal-epithelial characteristics and differentiation potential in vitro and in vivo. Oncotarget. 2016;7:25194-25207. - PubMed
  19. Schiewer MJ, Goodwin JF, Han S, et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discovery. 2012;2:1134-1149. - PubMed
  20. Centenera MM, Gillis JL, Hanson AR, et al. Evidence for efficacy of new Hsp90 inhibitors revealed by ex vivo culture of human prostate tumors. Clin Cancer Res. 2012;18:3562-3570. - PubMed
  21. Kersey PJ, Staines DM, Lawson D, et al. Ensembl genomes: an integrative resource for genome-scale data from non-vertebrate species. Nucleic Acids Res. 2012;40:D91-D97. - PubMed
  22. Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15-21. - PubMed
  23. Babraham Institute. 2019 Trim Galore. Accessed 2020. http://www.bioinformatics.babraham.ac.uk/projects/trim_galore - PubMed
  24. Anders S, Pyl PT, Huber W. HTSeq-a python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166-169. - PubMed
  25. Huber W, Carey VJ, Gentleman R, et al. Orchestrating high-throughput genomic analysis with Bioconductor. Nat Methods. 2015;12:115-121. - PubMed
  26. R Development Core Team. 2021. A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing. - PubMed
  27. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq. 2. Genome Biol. 2014;15:550. - PubMed
  28. Grasso CS, Wu YM, Robinson DR, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012;487:239-243. - PubMed
  29. Howard LE, Zhang J, Fishbane N, et al. Validation of a genomic classifier for prediction of metastasis and prostate cancer-specific mortality in African-American men following radical prostatectomy in an equal access healthcare setting. Prostate Cancer Prostatic Dis. 2020;23:419-428. - PubMed
  30. Chen WS, Aggarwal R, Zhang L, et al. Genomic drivers of poor prognosis and enzalutamide resistance in metastatic castration-resistant prostate cancer. Eur Urol. 2019;76:562-571. - PubMed
  31. Quigley DA, Dang HX, Zhao SG, et al. Genomic hallmarks and structural variation in metastatic prostate. Cancer Cell. 2018;174(758-69):e9-769. - PubMed
  32. Drake JM, Graham NA, Lee JK, et al. Metastatic castration-resistant prostate cancer reveals intrapatient similarity and interpatient heterogeneity of therapeutic kinase targets. Proc Natl Acad Sci USA. 2013;110:E4762-E4769. - PubMed
  33. Banerjee S, Buhrlage SJ, Huang HT, et al. Characterization of WZ4003 and HTH-01-015 as selective inhibitors of the LKB1-tumour-suppressor-activated NUAK kinases. Biochem J. 2014;457:215-225. - PubMed
  34. Centenera MM, Hickey TE, Jindal S, et al. A patient-derived explant (PDE) model of hormone-dependent cancer. Mol Oncol. 2018;12:1608-1622. - PubMed
  35. Shafi AA, Schiewer MJ, de Leeuw R, et al. Patient-derived models reveal impact of the tumor microenvironment on therapeutic response. Eur Urol Oncol. 2018;1:325-337. - PubMed
  36. Yang H, Wang X, Wang C, et al. Optimization of WZ4003 as NUAK inhibitors against human colorectal cancer. Eur J Med Chem. 2021;210:113080. - PubMed
  37. Hong W, Guan KL. The YAP and TAZ transcription co-activators: key downstream effectors of the mammalian Hippo pathway. Semin Cell Dev Biol. 2012;23:785-793. - PubMed
  38. Xiao W, Wang J, Ou C, et al. Mutual interaction between YAP and c-Myc is critical for carcinogenesis in liver cancer. Biochem Biophys Res Commun. 2013;439:167-172. - PubMed
  39. Ellwood-Yen K, Graeber TG, Wongvipat J, et al. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell. 2003;4:223-238. - PubMed
  40. Hawksworth D, Ravindranath L, Chen Y, et al. Overexpression of C-MYC oncogene in prostate cancer predicts biochemical recurrence. Prostate Cancer Prostatic Dis. 2010;13:311-315. - PubMed
  41. Kolliopoulos C, Raja E, Razmara M, et al. Transforming growth factor beta (TGFbeta) induces NUAK kinase expression to fine-tune its signaling output. The. J Biol Chem. 2019;294:4119-4136. - PubMed

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