Buchumschlag

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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Hauptverfasser: Xu, Jing (VerfasserIn) , Pfarr, Nicole (VerfasserIn) , Endris, Volker (VerfasserIn) , Mai, Elias K. (VerfasserIn) , Hanafiah, Nur Hafzan Md (VerfasserIn) , Giesen, Nicola (VerfasserIn) , Penzel, Roland (VerfasserIn) , Weichert, Wilko (VerfasserIn) , Ho, Anthony Dick (VerfasserIn) , Schirmacher, Peter (VerfasserIn) , Goldschmidt, Hartmut (VerfasserIn) , Andrulis, Mindaugas (VerfasserIn) , Raab, Marc-Steffen (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 15 May 2017
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
Volltext
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
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 09.10.2018
Beschreibung:Online Resource
ISSN:2157-9024
DOI:10.1038/oncsis.2017.36

Ähnliche Einträge