Expression of the serine/threonine kinase NEK2 is essential for entry into mitosis via its role in facilitating centrosome separation. Its overactivity can lead to tumorigenesis and drug resistance through the activation of several oncogenic pathways including AKT. While the cancer-enabling activities of NEK2 are documented in many malignancies, including correlations with poor survival in myeloma, breast, and non-small cell lung cancer, little is known about the role of NEK2 in lymphoma. Here, in tumors from patients with diffuse large B cell lymphoma (DLBCL), the most common, aggressive non-Hodgkin lymphoma, we found a high abundance of NEK2 mRNA and protein associated with an inferior overall survival. Using our recently developed NEK2 inhibitor, NBI-961, we discovered DLBCL cell lines and patient-derived cells exhibit a dependency on NEK2 for their viability. This compromised cell fitness was directly attributable to efficient NEK2 inhibition and proteasomal degradation by NBI-961. In a subset of particularly sensitive DLBCL cells, NBI-961 induced G2/mitosis arrest and apoptosis. In contrast, an existing indirect NEK2 inhibitor, INH154, did not prevent NEK2 autophosphorylation, induce NEK2 proteasomal degradation, or affect cell viability. Global proteomics and phospho-proteomics revealed that NEK2 orchestrates cell-cycle and apoptotic pathways through regulation of both known and new signaling molecules. We show the loss of NEK2 sensitized DLBCL to the chemotherapy agents doxorubicin and vincristine, and effectively suppressed tumor growth in mice. These studies establish the oncogenic activity of NEK2 in DLBCL and set the foundation for development of anti-NEK2 therapeutic strategies in this frequently refractory and relapse-prone cancer.

中文翻译：

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双功能抑制剂揭示 NEK2 作为淋巴瘤致癌途径的治疗靶点和调节剂

丝氨酸/苏氨酸激酶 NEK2 的表达对于通过其促进中心体分离的作用进入有丝分裂至关重要。它的过度活性可通过激活包括 AKT 在内的多种致癌途径导致肿瘤发生和耐药性。虽然 NEK2 的致癌活性在许多恶性肿瘤中都有记录，包括与骨髓瘤、乳腺癌和非小细胞肺癌的不良生存相关，但人们对 NEK2 在淋巴瘤中的作用知之甚少。在这里，在弥漫性大 B 细胞淋巴瘤 (DLBCL)（最常见的侵袭性非霍奇金淋巴瘤）患者的肿瘤中，我们发现高丰度的 NEK2 mRNA 和蛋白质与较差的总体生存率相关。使用我们最近开发的 NEK2 抑制剂 NBI-961，我们发现 DLBCL 细胞系和患者来源的细胞的活力依赖于 NEK2。这种受损的细胞适应性可直接归因于 NBI-961 的有效 NEK2 抑制和蛋白酶体降解。在特别敏感的 DLBCL 细胞亚群中，NBI-961 诱导 G2/有丝分裂停滞和细胞凋亡。相比之下，现有的间接 NEK2 抑制剂 INH154 不能阻止 NEK2 自磷酸化、诱导 NEK2 蛋白酶体降解或影响细胞活力。全局蛋白质组学和磷酸化蛋白质组学揭示，NEK2 通过调节已知和新的信号分子来协调细胞周期和凋亡途径。我们发现 NEK2 的缺失使 DLBCL 对化疗药物阿霉素和长春新碱敏感，并有效抑制了小鼠的肿瘤生长。这些研究确定了 NEK2 在 DLBCL 中的致癌活性，并为开发这种经常难治性且易复发的癌症的抗 NEK2 治疗策略奠定了基础。