Molecular signaling in multiple myeloma: association of RAS/RAF mutations and MEK/ERK pathway activation

J Xu,H Goldschmidt,W Weichert,P Schirmacher,N Lehners,A D Ho,R Penzel,N Pfarr,V Endris,E K Mai,M Andrulis,M S Raab,N H Md Hanafiah

doi:10.1038/oncsis.2017.36

Abstract

Multiple myeloma (MM) is a plasma cell malignancy that is still considered to be incurable in most cases. A dominant mutation cluster has been identified in RAS/RAF genes, emphasizing the potential significance of RAS/RAF/MEK/ERK signaling as a therapeutic target. As yet, however, the clinical relevance of this finding is unclear as clinical responses to MEK inhibition in RAS-mutant MM have been mixed. We therefore assessed RAS/RAF mutation status and MEK/ERK pathway activation by both targeted sequencing and phospho-ERK immunohistochemistry in 180 tissue biopsies from 103 patients with newly diagnosed MM (NDMM) and 77 patients with relapsed/refractory MM (rrMM). We found a significant enrichment of RAS/BRAF mutations in rrMM compared to NDMM (P=0.011), which was mainly due to an increase of NRAS mutations (P=0.010). As expected, BRAF mutations were significantly associated with activated downstream signaling. However, only KRAS and not NRAS mutations were associated with pathway activation compared to RAS/BRAFwt (P=0.030). More specifically, only KRASG12D and BRAFV600E were consistently associated with ERK activation (P<0.001 and P=0.006, respectively). Taken together, these results suggest the need for a more specific stratification strategy consisting of both confirmation of protein-level pathway activation as well as detailed RAS/RAF mutation status to allow for a more precise and more effective application of targeted therapies, for example, with BRAF/MEK inhibitors in MM.

Highlights

Multiple myeloma (MM) is a genetically highly heterogeneous disease
We focused on the correlation between individual RAS/BRAF mutations, assessed by massive parallel sequencing technology, and actual MEK/ERK pathway activation, analyzed by immunohistochemistry for phosphorylated ERK1/2 as an activation marker in primary MM patient biopsies.[10]
Patient characteristics Formalin-fixed, paraffin-embedded bone marrow or extramedullary tissue samples were available from a total of 180 patients, including 103 newly diagnosed MM patients and 77 relapsed/refractory MM patients who relapsed from previous lines of therapy containing at least one immunomodulatory drug and one proteasome inhibitor

Summary

INTRODUCTION

Multiple myeloma (MM) is a genetically highly heterogeneous disease. Despite tremendous improvement in response and survival rates due to novel agents and treatment strategies, MM is still considered to be incurable in the majority of patients.[1,2] Recent genomic studies suggest that MM is driven by mutations within the RAS signaling cascade. The RAS/MEK/ERK pathway is currently believed to be activated in about half of MM cases and is considered to be a major therapeutic target in MM like in many other cancers.[2,4,5,6] The activating BRAFV600E mutation has been reported to be of therapeutic relevance and clinical trials exploring BRAF and/or MEK inhibition in this genetic setting are ongoing.[7,8] So far, treatment of RAS/RAF mutant MM with the MEK inhibitor, trametinib, resulted in only moderate response rates; some responding patients experienced durable remissions.[4] This suggests the presence of varying degrees of dependency on MEK/ERK signaling in RAS-mutant MM. We focused on the correlation between individual RAS/BRAF mutations, assessed by massive parallel sequencing technology, and actual MEK/ERK pathway activation, analyzed by immunohistochemistry for phosphorylated ERK1/2 as an activation marker in primary MM patient biopsies.[10]

RESULTS AND DISCUSSION

CONCLUSION

CONFLICT OF INTEREST