Dataset Information

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

ABSTRACT: 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.

SUBMITTER: McCrury M

PROVIDER: S-EPMC10932871 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

McCrury Mason M Swafford Kennith K Shuttleworth Sydnye L SL Mehdi Syed Hassan SH Acharya Baku B Saha Debasmita D Naceanceno Kevin K Byrum Stephanie D SD Storey Aaron J AJ Xu Ying-Zhi YZ Doshier Claire C Patel Vijay V Post Ginell R GR De Loose Annick A Rodriguez Analiz A Shultz Leonard D LD Zhan Fenghuang F Yoon Donghoon D Frett Brendan B Kendrick Samantha S

Molecular cancer therapeutics 20240301 3

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, litt ...[more]

PMID: 37816504

Similar Datasets

Project description:Cholangiocarcinoma (CCA) is a primary malignant tumor of the liver, typically diagnosed in advanced stages. Surgical resection remains the principal treatment method in clinical practice. Regrettably, the majority of patients receive their diagnosis at an advanced stage, making surgical intervention unfeasible. While chemotherapy serves as the main palliative treatment for advanced CCA, its effectiveness is significantly limited due to the rapid development of chemoresistance. Studying the pathogenesis of CCA and new resistance targets is crucial for improving clinical outcomes. In our current study, we first identified the expression of SLC16A1 in the transcriptome and proteome of human tumors and found abnormal expression of SLC16A1 in various human cancers. Subsequently, we focused our attention on the role of SLC16A1 in CCA. Utilizing bioinformatics analysis, we pioneered the identification of the clinical significance of SLC16A1 in this type of cancer. Specifically, higher expression levels of SLC16A1 were observed in CCA patients with venous invasion and higher T and M stages. Additionally, patients with higher SLC16A1 expression had poorer prognoses. These results suggest the oncogenic role of SLC16A1 in CCA. Further immune infiltration analysis revealed a significant correlation between SLC16A1 and the infiltration levels of cells like neutrophils and macrophages in the tumor microenvironment, indicating SLC16A1's potential involvement in regulating the tumor immune microenvironment of CCA. Moreover, results from functional and pathway enrichment analyses revealed that SLC16A1 might affect clinical outcomes in CCA patients by participating in drug metabolism processes. Finally, through further in vitro and in vivo experiments, we confirmed that SLC16A1, as an oncogene in CCA, promotes the growth of CCA cells and chemoresistance. Knocking down SLC16A1 inhibited the growth of CCA cells and enhanced their sensitivity to 5-Fluorouracil (5-FU). Overall, this study reveals the key role of SLC16A1 in the development of CCA and highlights its significance as a potential target for improving treatment efficacy and chemotherapy sensitivity.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets