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

in Molecular cancer therapeutics by Mason McCrury, Kennith Swafford, Sydnye L Shuttleworth, Syed Hassan Mehdi, Baku Acharya, Debasmita Saha, Kevin Naceanceno, Stephanie D Byrum, Aaron J Storey, Ying-Zhi Xu, Claire Doshier, Vijay Patel, Ginell R Post, Annick De Loose, Analiz Rodriguez, Leonard D Shultz, Fenghuang Zhan, Donghoon Yoon, Brendan Frett, Samantha Kendrick

TLDR

  • The study found that a protein called NEK2 is important for a process called mitosis, which is when cells divide. When NEK2 is overactive, it can cause tumors and make them resistant to drugs. The study also found that NEK2 is important for DLBCL, a type of cancer that affects the lymph nodes. The study used a special drug to block NEK2 and found that it killed the cancer cells. The study also found that NEK2 is important for other signaling molecules that help cells divide and die. The study suggests that NEK2 could be a target for new treatments for DLBCL.

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.

Overview

  • The study investigates the role of the serine/threonine kinase never in mitosis gene A (NIMA)-related kinase 2 (NEK2) in diffuse large B-cell lymphoma (DLBCL), the most common aggressive non-Hodgkin lymphoma. The study tests the hypothesis that NEK2 is essential for entry into mitosis and that its overactivity can lead to tumorigenesis and drug resistance. The methodology used includes analyzing NEK2 mRNA and protein levels in DLBCL tumors, testing the dependency of DLBCL cell lines and patient-derived cells on NEK2 for viability, and using global proteomics and phospho-proteomics to identify signaling molecules regulated by NEK2. The primary objective of the study is to establish the oncogenic activity of NEK2 in DLBCL and set the foundation for the development of anti-NEK2 therapeutic strategies in this cancer.

Comparative Analysis & Findings

  • The study found a high abundance of NEK2 mRNA and protein in DLBCL tumors, which was associated with an inferior overall survival. The study also discovered that DLBCL cell lines and patient-derived cells exhibit a dependency on NEK2 for their viability, which 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. The study also revealed that NEK2 orchestrates cell-cycle and apoptotic pathways through regulation of both known and new signaling molecules. The study establishes the oncogenic activity of NEK2 in DLBCL and sets the foundation for the development of anti-NEK2 therapeutic strategies in this cancer.

Implications and Future Directions

  • The study's findings suggest that NEK2 is essential for entry into mitosis and that its overactivity can lead to tumorigenesis and drug resistance in DLBCL. The study also highlights the potential of NEK2 as a therapeutic target in DLBCL. Future research directions could include further investigation of the mechanisms underlying NEK2-mediated tumorigenesis and drug resistance, as well as the development of more specific and potent NEK2 inhibitors. The study also suggests that NEK2 may play a role in other cancers, and further research could investigate its role in other malignancies.
Read Full Article