Fu Weiwei, Zhao Megan T, Driver Lucy M, Schirmer Amelia U, Yin Qi, You Sungyong, Freedland Stephen J, DiGiovanni John, Drewry David H, Macias Everardo
Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA.
Mol Carcinog. 2022 Mar;61(3):334-345. doi: 10.1002/mc.23374. Epub 2021 Nov 24.
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.
前列腺癌（PC）治疗领域的当前进展已成功减缓了PC的进展并延长了预期寿命；然而，对于晚期转移性去势抵抗性PC（mCRPC）仍没有治愈性的治疗方法。大多数治疗选择都针对雄激素受体，许多PC最终会对其产生抗性。因此，迫切需要识别和验证用于治疗PC的新分子靶点。我们发现，与正常组织相比，NUAK家族激酶2（NUAK2）在PC和mCRPC中的表达升高，且表达与转移风险增加相关。鉴于这一观察结果，并且由于NUAK2作为一种激酶是可作用的，我们评估了NUAK2作为PC分子靶点的潜力。NUAK2是一种应激反应激酶，在YAP共转录致癌基因的激活中也发挥作用。结合药理学和遗传学方法来调节NUAK2，我们发现在体外靶向NUAK2会导致PC细胞的增殖、三维肿瘤球体生长和基质胶侵袭减少。对用NUAK2小分子抑制剂HTH-02-006处理的PC细胞进行差异基因表达分析表明，抑制NUAK2会导致在抑制NUAK2后E2F、EMT和MYC标志性基因集的下调。在同基因异种移植模型和根治性前列腺切除术患者来源的外植体中，抑制NUAK2减缓了肿瘤生长和增殖速率。从机制上讲，HTH-02-006处理导致YAP失活以及NUAK2和MYC蛋白水平下调。我们的结果表明，NUAK2是PC的一个新的可作用分子靶点，值得进一步探索。
