ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment.
ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment.
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ERK信号介导骨髓微环境中免疫调节药物的耐药性
DOI：
10.1126/sciadv.abg2697
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发表时间：
2021-06
期刊：
影响因子：
13.6
通讯作者：
Anderson KC
中科院分区：
文献类型：
--
作者：
Liu J;Hideshima T;Xing L;Wang S;Zhou W;Samur MK;Sewastianik T;Ogiya D;An G;Gao S;Yang L;Ji T;Bianchi G;Wen K;Tai YT;Munshi N;Richardson P;Carrasco R;Cang Y;Anderson KC
阻断MEK-ERK通路可克服骨髓微环境中骨髓瘤细胞对免疫调节药物的耐药性。免疫调节药物(IMids)显著改善了多发性骨髓瘤(MM)患者的预后；然而，对IMids的抵抗通常是疾病复发的基础。在此，我们发现MM细胞中肿瘤坏死因子受体相关因子2(TRAF2)基因敲除(KD)/敲除(KO)通过激活非规范核因子κB(NF-κB)和细胞外信号调节激酶(ERK)信号转导介导IMID抵抗。在MM骨髓基质细胞上清液中，肿瘤坏死因子-α可诱导MM细胞蛋白酶体降解TRAF2、非规范的NF-ERKB及其下游的κ信号，而IL-6则直接激活ERK1。多发性骨髓瘤患者样本的RNA测序显示，来那度胺维持治疗复发时，ERK通路几乎普遍激活，证实了其临床意义。联合应用MEK抑制剂可在体内外恢复TRAF2 KO细胞对IMID的敏感性。我们的研究为MEK抑制剂的临床试验提供了框架，以克服骨髓微环境中的IMiD耐药性，改善MM患者的预后。
Blocking of MEK-ERK pathway overcomes myeloma cells resistance to immunomodulatory drugs in the bone marrow microenvironment. Immunomodulatory drugs (IMiDs) have markedly improved patient outcome in multiple myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease. Here, we identify that tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) knockdown (KD)/knockout (KO) in MM cells mediates IMiD resistance via activation of noncanonical nuclear factor κB (NF-κB) and extracellular signal–regulated kinase (ERK) signaling. Within MM bone marrow (BM) stromal cell supernatants, TNF-α induces proteasomal degradation of TRAF2, noncanonical NF-κB, and downstream ERK signaling in MM cells, whereas interleukin-6 directly triggers ERK activation. RNA sequencing of MM patient samples shows nearly universal ERK pathway activation at relapse on lenalidomide maintenance therapy, confirming its clinical relevance. Combination MEK inhibitor treatment restores IMiD sensitivity of TRAF2 KO cells both in vitro and in vivo. Our studies provide the framework for clinical trials of MEK inhibitors to overcome IMiD resistance in the BM microenvironment and improve patient outcome in MM.
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