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

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

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


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.

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