Molecular signaling in multiple myeloma: association of RAS/RAF mutations and MEK/ERK pathway activation
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 relev...
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| Hauptverfasser: | , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
15 May 2017
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| In: |
Oncogenesis
Year: 2017, Jahrgang: 6, Heft: 5 |
| ISSN: | 2157-9024 |
| DOI: | 10.1038/oncsis.2017.36 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1038/oncsis.2017.36 Verlag, kostenfrei, Volltext: https://www.nature.com/articles/oncsis201736 
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| Verfasserangaben: | 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 and M.S. Raab |
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| 520 | |a 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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