A melanocyte lineage program confers resistance to MAP kinase pathway inhibition.
A melanocyte lineage program confers resistance to MAP kinase pathway inhibition.
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DOI：
10.1038/nature12688
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发表时间：
2013-12-05
期刊：
影响因子：
64.8
通讯作者：
Garraway, Levi A.
中科院分区：
文献类型：
--
作者：
Johannessen, Cory M.;Johnson, Laura A.;Piccioni, Federica;Townes, Aisha;Frederick, Dennie T.;Donahue, Melanie K.;Narayan, Rajiv;Flaherty, Keith T.;Wargo, Jennifer A.;Root, David E.;Garraway, Levi A.
BRAFV 600 E突变型恶性黑色素瘤依赖于RAF/MEK/ERK（MAPK）信号传导进行肿瘤细胞生长。RAF和MEK抑制剂在BRAFV 600 E黑色素瘤中显示出显著的临床疗效;然而，对这些药物的耐药性仍然是一个巨大的挑战。耐药机制的全球表征可能会为开发更有效的治疗组合提供信息。在这里，我们通过在用RAF、MEK、ERK或组合RAF/MEK抑制剂处理的BRAFV 600 E黑素瘤细胞系中单独表达> 15，500个基因来进行系统的功能获得性抗性研究。这些研究揭示了一个以前与耐药性无关的环AMP依赖性黑素细胞信号网络，包括G蛋白偶联受体、腺苷酸环化酶、蛋白激酶A和cAMP反应元件结合蛋白（CREB）。对BRAFV 600 E黑色素瘤患者活检的初步分析显示，磷酸化（活性）CREB被RAF/MEK抑制剂抑制，但在复发性肿瘤中恢复。MAP激酶和cAMP通路下游激活的转录因子的表达也赋予抗性，包括c-FOS、NR 4A 1、NR 4A 2和MITF。MAP激酶通路和组蛋白去乙酰化酶抑制剂的联合治疗抑制了MITF表达和cAMP介导的耐药性。总的来说，这些数据表明，黑素细胞谱系依赖性的致癌失调可导致对RAF/MEK/ERK抑制的抗性，这可通过组合信号传导和染色质定向治疗来克服。
BRAFV600E-mutant malignant melanomas depend on RAF/MEK/ERK (MAPK) signaling for tumor cell growth. RAF and MEK inhibitors show remarkable clinical efficacy in BRAFV600E melanoma; however, resistance to these agents remains a formidable challenge. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here, we performed systematic gain-of-function resistance studies by expressing >15,500 genes individually in a BRAFV600E melanoma cell line treated with RAF, MEK, ERK, or combined RAF/MEK inhibitors. These studies revealed a cyclic AMP-dependent melanocytic signaling network not previously associated with drug resistance, including G-protein coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). Preliminary analysis of biopsies from BRAFV600E melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF/MEK-inhibition but restored in relapsing tumors. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS, NR4A1, NR4A2 and MITF. Combined treatment with MAP kinase pathway and histone deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF/MEK/ERK inhibition, which may be overcome by combining signaling- and chromatin-directed therapeutics.
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微观筛查显示黑色素瘤中治疗反应的遗传修饰剂。
影响因子：
7.3
作者：
Wood KC;Konieczkowski DJ;Johannessen CM;Boehm JS;Tamayo P;Botvinnik OB;Mesirov JP;Hahn WC;Root DE;Garraway LA;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
4.3
作者：
Yokoyama, Satoru;Feige, Erez;Fisher, David E.
通讯作者：
Fisher, David E.
影响因子：
64.8
作者：
Solit, DB;Garraway, LA;Rosen, N
通讯作者：
Rosen, N
影响因子：
11.2
作者：
Jané-Valbuena J;Widlund HR;Perner S;Johnson LA;Dibner AC;Lin WM;Baker AC;Nazarian RM;Vijayendran KG;Sellers WR;Hahn WC;Duncan LM;Rubin MA;Fisher DE;Garraway LA
通讯作者：
Garraway LA
影响因子：
56.9
作者：
CREWS, CM;ALESSANDRINI, A;ERIKSON, RL
通讯作者：
ERIKSON, RL