Destabilizing NEK2 May Overcome Resistance to Treatment in Multiple Myeloma
Posted: Monday, September 10, 2018
It is well accepted among the oncology community that patients with multiple myeloma harbor several subclones that may change over time. The coexistence of multiple subclones with a high or low chromosomal instability (CIN) signature causes heterogeneity and drug resistance with consequent disease relapse. With that in mind, a study published in the Journal of Clinical Investigation centers on the hypothesis that destabilizing NEK2 overcomes resistance to proteasome inhibition in multiple myeloma. NEK2 is the most significant gene associated with drug resistance and poor outcomes, based on almost 2,500 microarrays in multiple myeloma and other cancers.
In this study, using a tandem affinity purification–mass spectrometry technique, Reinaldo Franqui-Machin, MD, of the University of Iowa, and colleagues, found that the CIN gene NEK2 was bound to the deubiquitinase USP7. Binding to USP7 prevented NEK2 ubiquitination, resulting in NEK2 stabilization. They also found that newly diagnosed patients with multiple myeloma who demonstrated activated NF-κB signaling through increased NEK2 activity had poorer event-free and overall survival, based on multiple independent clinical cohorts. They also discovered that NEK2-activated heparanase, a secreted enzyme that is responsible for bone destruction in an NF-κB–dependent manner.
“Our data present a potentially novel mechanism by which NEK2 drives drug resistance in multiple myeloma,” concluded the investigators. “We postulate that therapeutic targeting of NEK2, using NEK2 inhibitors, in patients with multiple myeloma may be most effective as an adjuvant therapy when tumor mass is already extremely debulked.”