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Titel:

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

Dokumenttyp:
Journal Article; Article
Autor(en):
Xu, J; Pfarr, N; Endris, V; Mai, E K; Md Hanafiah, N H; Lehners, N; Penzel, R; Weichert, W; Ho, A D; Schirmacher, P; Goldschmidt, H; Andrulis, M; Raab, M S
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.
Zeitschriftentitel:
Oncogenesis
Jahr:
2017
Band / Volume:
6
Heft / Issue:
5
Seitenangaben Beitrag:
e337
Sprache:
eng
Volltext / DOI:
doi:10.1038/oncsis.2017.36
PubMed:
http://view.ncbi.nlm.nih.gov/pubmed/28504689
Print-ISSN:
2157-9024
TUM Einrichtung:
Institut für Allgemeine Pathologie und Pathologische Anatomie
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