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

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

doi:10.1038/oncsis.2017.36

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

Oncogenesis. 2017 May 15;6(5):e337. doi: 10.1038/oncsis.2017.36.

Authors

J Xu^{1

2

3}, N Pfarr², V Endris², E K Mai³, N H Md Hanafiah¹, N Lehners^{1

3}, R Penzel², W Weichert², A D Ho³, P Schirmacher², H Goldschmidt^{3

4}, M Andrulis², M S Raab^{1

3}

Affiliations

¹ Max Eder Group Experimental Therapies for Hematologic Malignancies, Heidelberg University Hospital and German Cancer Research Center (DKFZ), Heidelberg, Germany.
² Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
³ Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.
⁴ National Center for Tumor Diseases (NCT), Heidelberg, Germany.

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/BRAF^wt (P=0.030). More specifically, only KRAS^G12D and BRAF^V600E 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.