Molecular signaling in multiple myeloma

• Verfasst von: Xu, Jing [VerfasserIn]
• Verfasst von: Pfarr, Nicole [VerfasserIn]
• Verfasst von: Endris, Volker [VerfasserIn]
• Verfasst von: Mai, Elias K. [VerfasserIn]
• Verfasst von: Hanafiah, Nur Hafzan Md [VerfasserIn]
• Verfasst von: Giesen, Nicola [VerfasserIn]
• Verfasst von: Penzel, Roland [VerfasserIn]
• Verfasst von: Weichert, Wilko [VerfasserIn]
• Verfasst von: Ho, Anthony Dick [VerfasserIn]
• Verfasst von: Schirmacher, Peter [VerfasserIn]
• Verfasst von: Goldschmidt, Hartmut [VerfasserIn]
• Verfasst von: Andrulis, Mindaugas [VerfasserIn]
• Verfasst von: Raab, Marc-Steffen [VerfasserIn]
• Titel: Molecular signaling in multiple myeloma
• Titelzusatz: association of RAS/RAF mutations and MEK/ERK pathway activation
• Verf.angabe: 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
• E-Jahr: 2017
• Jahr: 15 May 2017
• Umfang: 5 S.
• Fussnoten: Gesehen am 09.10.2018
• Titel Quelle: Enthalten in: Oncogenesis
• Ort Quelle: [S.l.] : Nature Publ., 2012
• Jahr Quelle: 2017
• Band/Heft Quelle: 6(2017), 5, Artikel-ID e337
• ISSN Quelle: 2157-9024
• DOI: doi:10.1038/oncsis.2017.36
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1581695497

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.