Destabilizing NEK2 overcomes resistance to proteasome inhibition in multiple myeloma

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Drug resistance is a major challenge in multiple myeloma treatment, often driven by tumor heterogeneity and chromosomal instability (CIN).
• Understanding the molecular mechanisms underlying subclone evolution and drug resistance is crucial for developing effective therapies.

Purpose of the Study:

• To investigate the role of the CIN gene NEK2 in multiple myeloma.
• To identify NEK2-interacting proteins and elucidate its role in drug resistance and disease progression.
• To evaluate the therapeutic potential of targeting NEK2 and its interacting partners in multiple myeloma.

Main Methods:

• Tandem affinity purification-mass spectrometry (TAP-MS) to identify NEK2-interacting proteins.
• Western blotting and ubiquitination assays to assess NEK2 stabilization.
• Analysis of the NF-κB signaling pathway and its downstream targets, including heparanase.
• Evaluation of NEK2 and USP7 inhibitors in preclinical multiple myeloma models.

Main Results:

• NEK2 was found to bind to the deubiquitinase USP7, which prevents NEK2 ubiquitination and leads to NEK2 stabilization.
• Increased NEK2 kinase levels activate the NF-κB signaling pathway via the PP1α/AKT axis.
• Activated NF-κB signaling through NEK2 correlates with poorer survival in newly diagnosed myeloma patients.
• NEK2 activates heparanase in an NF-κB-dependent manner, contributing to bone destruction.
• NEK2 and USP7 inhibitors demonstrated significant efficacy in inhibiting myeloma cell growth and overcoming drug resistance in mouse models.

Conclusions:

• The NEK2-USP7 interaction stabilizes NEK2, promoting NF-κB pathway activation and contributing to multiple myeloma progression and drug resistance.
• Targeting NEK2 and USP7 represents a promising therapeutic strategy for overcoming drug resistance and improving outcomes in multiple myeloma.