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
Max Eder Group Experimental Therapies for Hematologic Malignancies, Heidelberg University Hospital and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Oncogenesis. 2017 May 15;6(5):e337. doi: 10.1038/oncsis.2017.36.
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 (P=0.030). More specifically, only KRAS and BRAF 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.
多发性骨髓瘤（MM）是一种浆细胞恶性肿瘤，在大多数情况下仍被认为是无法治愈的。已在RAS/RAF基因中鉴定出一个主要的突变簇，这突出了RAS/RAF/MEK/ERK信号作为治疗靶点的潜在重要性。然而，到目前为止，这一发现的临床相关性尚不清楚，因为RAS突变型MM对MEK抑制的临床反应不一。因此，我们通过靶向测序和磷酸化ERK免疫组化评估了103例新诊断MM（NDMM）患者和77例复发/难治性MM（rrMM）患者的180份组织活检样本中的RAS/RAF突变状态和MEK/ERK通路激活情况。我们发现，与NDMM相比，rrMM中RAS/BRAF突变显著富集（P=0.011），这主要是由于NRAS突变增加（P=0.010）。正如预期的那样，BRAF突变与下游信号激活显著相关。然而，与RAS/BRAF相比，只有KRAS而非NRAS突变与通路激活相关（P=0.030）。更具体地说，只有KRAS和BRAF与ERK激活始终相关（分别为P<0.001和P=0.006）。综上所述，这些结果表明需要一种更具体的分层策略，包括确认蛋白质水平的通路激活以及详细的RAS/RAF突变状态，以便更精确、更有效地应用靶向治疗，例如在MM中使用BRAF/MEK抑制剂。
