Targeting MK2 Is a Novel Approach to Interfere in Multiple Myeloma

Mengjie Guo,Miaomiao Shao,Yuxia Yuan,Yuqi Zhu,Chunyan Gu,Zhimin Fan,Jinjun Qian,Fei Li,Jianhao Hou,Dongdong Sun,Rongfang Wei,Ye Yang,Yan Zhu

doi:10.3389/fonc.2019.00722

Abstract

MAPKAPK2 (MK2), the direct substrate of p38 MAPK, has been well-acknowledged as an attractive drug target for cancer therapy. However, few studies have assessed the functions of it in multiple myeloma (MM). In the present study, MK2 expression of MM patients was analyzed by gene expression profiling (GEP) and array-based comparative genomic hybridization (aCGH). Several experiments in vitro including MTT assay, Western blot and flow cytometry analysis were performed to identify the function of MK2 in MM. In addition, we conducted mouse survival experiments to explain the effects of MK2 on MM in vivo. mRNA level of MK2 and chromosomal gain of MK2 locus in MM cells significantly increased compared to normal samples. Furthermore, MM patients with high expression of MK2 were associated with a poor outcome. Follow-up studies showed that MK2 exerted a remarkably positive effect on MM cell proliferation and drug-resistance. Further exploration focusing on MK2 inhibitor IV revealed its inhibitory action on MM growth and drug-resistance, as well as improving survival in mouse models. In addition, a combination of MK2 inhibitor IV and the key MM therapeutic agents including bortezomib, doxorubicin, or dexamethasone facilitated curative effects on inhibiting MM cell proliferation. Taken together, our study reveals the clinical relevance of MK2 inhibition in MM and demonstrates that targeting MK2 may afford a new therapeutic approach to MM.

Highlights

Multiple myeloma (MM) is the second most prevalent hematologic malignancy derived from neoplastic growth of bone marrow plasma cells
Using the gene expression profiling (GEP) database collected from NIH Gene Expression Omnibus GSE2658 as a discovery tool, we found that MK2 expression levels exhibited a dramatic upward trend from normal plasma cells (NP, n = 22), monoclonal gammopathy of undetermined significance cells (MGUS, n = 44), to newly diagnosed myeloma patient plasma cells (n = 351) (Figure 1A)
Kaplan-Meier survival curves showed that increment of MK2 expression was linked with an apparently shorter response duration of both event free (EF) and overall survival (OS) in total therapy 2 (TT2) (Total Therapy 2) cohort, respectively (Figures 1C,D)

Summary

Introduction

Multiple myeloma (MM) is the second most prevalent hematologic malignancy derived from neoplastic growth of bone marrow plasma cells. Chemotherapy has been reported to interfere with the function of cellular machineries (like DNA replication and cell division), and is regarded as one of the useful therapeutic methods for MM; more and more novel agents are developed and tested [1]. Overexpression of MK2 could be linked with MM drug resistance and relapse, due to the fact that p38-MAPKAPK2Hsp signaling preserves the survival of cancer stem cells [6]. It is conceivable that MK2 may act as a powerful hallmark of cancer cells and inhibiting MK2 could disrupt tumor growth [7], which provides new avenues to explore the response of cancers to their therapeutic agents

Methods

Results

Conclusion