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

Oncogenesis
J XuM S Raab

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/BRAF(wt) (P=0.030). More specifically, only KRAS(G12D) and BRAF(V600E) 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 s...Continue Reading

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Citations

Apr 21, 2018·British Journal of Haematology·Craig T Wallington-BeddoeStuart M Pitson
Jul 12, 2018·Journal of Oncology Practice·Kenneth C Anderson
Apr 25, 2018·Nature Reviews. Clinical Oncology·Shaji K Kumar, S Vincent Rajkumar
May 9, 2019·Clinical Epigenetics·Zhenhai LiChor Sang Chim
Jun 16, 2019·International Journal of Molecular Sciences·Monserrat Olea-FloresNapoleón Navarro-Tito
Jun 22, 2019·Oxidative Medicine and Cellular Longevity·Dongdong WuYanzhang Li
Oct 28, 2019·Breast Cancer Research and Treatment·Nathan M MerrillMatthew B Soellner
Jul 19, 2020·International Journal of Molecular Sciences·Sabah AkhtarShahab Uddin
Jan 30, 2019·Annual Review of Medicine·Chutima Kunacheewa, Robert Z Orlowski
Jul 11, 2020·Cancer Metastasis Reviews·Tamás TakácsVirag Vas
Apr 29, 2018·Cancer Research·Niels van NieuwenhuijzenVictor Peperzak
Dec 9, 2020·Cancer Letters·Pegah AbdollahiMagne Børset
May 1, 2021·Cancers·Lukas JohnMarc-Steffen Raab
Apr 20, 2021·Frontiers in Cell and Developmental Biology·Shuang-Shuang DongBin-Bin Liu
May 20, 2021·Leukemia·Fengjuan FanKlaus Podar
Jun 3, 2021·Cancers·Mélody CaillotBrigitte Sola

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Methods Mentioned

BETA
biopsies

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