Bifunctional Inhibitor Reveals NEK2 as a Therapeutic Target and Regulator of Oncogenic Pathways in Lymphoma

被引：8

作者：

McCrury, Mason ^{[1
]}

Swafford, Kennith ^{[1
]}

Shuttleworth, Sydnye L. ^{[1
]}

Mehdi, Syed Hassan ^{[2
]}

Acharya, Baku ^{[3
]}

Saha, Debasmita ^{[3
]}

Naceanceno, Kevin ^{[1
]}

Byrum, Stephanie D. ^{[1
,4
]}

Storey, Aaron J. ^{[1
]}

Xu, Ying-Zhi ^{[1
]}

Doshier, Claire ^{[1
]}

Patel, Vijay ^{[5
]}

Post, Ginell R. ^{[5
]}

De Loose, Annick ^{[6
]}

Rodriguez, Analiz ^{[6
]}

Shultz, Leonard D. ^{[7
]}

Zhan, Fenghuang ^{[2
,8
]}

Yoon, Donghoon ^{[2
]}

Frett, Brendan ^{[3
]}

Kendrick, Samantha ^{[1
,9
]}

机构：

[1] Univ Arkansas Med Sci, Dept Biochem & Mol Biol, Little Rock, AR USA

[2] Univ Arkansas Med Sci, Myeloma Ctr, Little Rock, AR USA

[3] Univ Arkansas Med Sci, Dept Pharmaceut Sci, Little Rock, AR USA

[4] Arkansas Childrens Res Inst, Little Rock, AR USA

[5] Univ Arkansas Med Sci, Dept Pathol, Little Rock, AR USA

[6] Univ Arkansas Med Sci, Dept Neurosurg, Little Rock, AR USA

[7] Jackson Lab, Bar Harbor, ME USA

[8] Univ Arkansas Med Sci, Dept Internal Med, Little Rock, AR USA

[9] Univ Arkansas Med Sci, 4301 West Markham,Slot 516, Little Rock, AR 72205 USA

来源：

MOLECULAR CANCER THERAPEUTICS | 2024年 / 23卷 / 03期

基金：

美国国家卫生研究院;

关键词：

B-CELL LYMPHOMA; GENE-EXPRESSION; TUMOR PROGRESSION; DRUG-RESISTANCE; PROTEIN-KINASE; R-CHOP; SUBTYPES; CARDIOTOXICITY; CLASSIFICATION; CHEMOTHERAPY;

D O I：

10.1158/1535-7163.MCT-23-0299

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Expression of the serine/threonine kinase never in mitosis gene A (NIMA)-related kinase 2 (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. Although 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 that 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.

引用

页码：316 / 329

页数：14