Abstract 3391: Overexpression of Nek2 promotes bortezomib resistance in multiple myeloma cells.

Abstract

Abstract Drug resistance is a major complication in cancer therapy but the molecular mechanisms driving both innate and acquired drug resistance still remain largely unknown for many anti-cancer agents. Microarray analyses on paired primary multiple myeloma samples at baseline and after therapy or at relapse showed that the mitotic kinase NEK2 was one of the most up-regulated genes in myeloma cells after high-dose chemotherapy or at relapse. Nek2 is a Serine/Threonine kinase that is activated during mitosis and is associated centrosome function and structure at the G2/M transition. A role for Nek2 has been suggested in the separation of centrosomes as well as promoting cell cycle from G2 phase to M phase but no role for Nek2 in mediating drug resistance has been described. By analyzing the published (> 2,500) microarrays and clinical datasets, we found that NEK2 expression is increased in many malignancies, and that high expression of NEK2 was associated with a shorter event-free and overall survival. Moreover, NEK2 expression was typically increased in tumors with aggressive subtype and advanced stage. Our studies in myeloma cells indicate that over-expressing NEK2 results in enhanced cell proliferation and drug resistance, whereas knockdown of NEK2 induced significant cancer cell death and growth inhibition. Nek2 transfected myeloma cell lines ARP1, H929 and KMS28PE were used to investigate Nek2’s function relative to bortezomib resistance. We found that Nek2 over-expression significantly elevated the proteasome activity of transfected cells leading to decreased activity of Bortezomib in these cells. Using novel small molecule Nek2 inhibitors developed in our lab, we demonstrated efficient inhibition of proteasome activity in Nek2 over-expressing cancer cell lines. The treatment of cell with our lead compounds significantly inhibited the degradation of some proteasome targeted cell cycle regulators. Further, the combinations of these Nek2 inhibitors and bortezomib, greatly elevated the efficiency of bortezomib in decreasing the proteasome activity in vitro. The treatment with these novel Nek2 inhibitors successfully rescued the drug resistance in Nek2 over-expressed cells, indicating a potential therapy for bortezomib resistant myeloma patients. We conclude that NEK2 represents a predictor for drug resistance and poor prognosis in cancers and could be a potential target for cancer therapy. Citation Format: Jessica Flory, Rachel Brog, Ling Yao Meng, Lee Call, Hariprasad Vankayalapati, Guido Tricot, Fenghuang Zhan, David J. Bearss. Overexpression of Nek2 promotes bortezomib resistance in multiple myeloma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3391. doi:10.1158/1538-7445.AM2013-3391