Inhibition of Nek2 by small molecules affects proteasome activity

Background: Nek2 is a serine/threonine kinase localized to the centrosome. It promotes cell cycle progression from G2 to M by inducing centrosome separation. Recent studies have shown that high Nek2 expression is correlated with drug resistance in multiple myeloma patients.

Materials and methods: To investigate the role of Nek2 in bortezomib resistance, we ectopically overexpressed Nek2 in several Cancer cell lines, including multiple myeloma lines. Small-molecule inhibitors of Nek2 were discovered using an in-house library of compounds. We tested the inhibitors on Proteasome and cell cycle activity in several cell lines.

Results: Proteasome activity was elevated in Nek2-overexpressing cell lines. The Nek2 inhibitors inhibited Proteasome activity in these Cancer cell lines. Treatment with these inhibitors resulted in inhibition of proteasome-mediated degradation of several cell cycle regulators in HeLa cells, leaving them arrested in G2/M. Combining these Nek2 inhibitors with bortezomib increased the efficacy of bortezomib in decreasing Proteasome activity in vitro. Treatment with these novel Nek2 inhibitors successfully mitigated drug resistance in bortezomib-resistant multiple myeloma.

Conclusion: Nek2 plays a central role in proteasome-mediated cell cycle regulation and in conferring resistance to bortezomib in Cancer cells. Taken together, our results introduce Nek2 as a therapeutic target in bortezomib-resistant multiple myeloma.