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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Fu, W; Zhao, MT; Driver, LM; Schirmer, AU; Yin, Q; You, S; Freedland, SJ; DiGiovanni, J; Drewry, DH; Macias, E

Published Date

  • March 2022

Published In

Volume / Issue

  • 61 / 3

Start / End Page

  • 334 - 345

PubMed ID

  • 34818445

Electronic International Standard Serial Number (EISSN)

  • 1098-2744

Digital Object Identifier (DOI)

  • 10.1002/mc.23374

Language

  • eng

Conference Location

  • United States