系統(tǒng)性研究腫瘤耐藥性的新方法

2013年11月12日 | Filed under: 抗腫瘤藥,文獻(xiàn)綜合 | Posted by: 編輯 D

作者：呂順

眾所周知，許多抗腫瘤藥物能有效地抑制腫瘤的生長，但最常見的挑戰(zhàn)是隨后的復(fù)發(fā)。以黑色素瘤為例，大約50％的腫瘤發(fā)現(xiàn)BRAF基因突變，靶向BRAF突變基因通路的藥物起初能有效地治療黑色素瘤，但是大約9個月以后通常開始復(fù)發(fā)，并且產(chǎn)生耐藥性。以勞倫?所羅門（Levi Garranway）為首的麻省理工學(xué)院研究團(tuán)隊最近在《自然》雜志報道一種新型系統(tǒng)性地研究腫瘤耐藥機(jī)制的方法。采用這個新方法，該研究團(tuán)隊成功發(fā)現(xiàn)黑色素瘤的耐藥機(jī)理，并且找到克服黑色素瘤耐藥的新途徑。

該團(tuán)隊表達(dá)了超過15,000個基因，并采用能啟動單個基因表達(dá)的ORF（Open Reading Frame）基因表達(dá)庫，以便系統(tǒng)地模擬細(xì)胞產(chǎn)生耐藥的機(jī)制。隨后課題組在BRAF突變的黑色素瘤細(xì)胞中一個個地激活每一個基因，而后觀察細(xì)胞對治療BRAF突變的黑色素瘤常見藥物的敏感性。由此發(fā)現(xiàn)不同基因突變對可能發(fā)生耐藥的一個完整列表。結(jié)果發(fā)現(xiàn)，負(fù)責(zé)正常皮膚細(xì)胞生長的一個關(guān)鍵通路是黑色素瘤耐藥的最常見機(jī)制。

【原文摘要】

A melanocyte lineage program confers resistance to MAP kinase pathway inhibition

Malignant melanomas harbouring point mutations (Val600Glu) in the serine/threonine-protein kinase BRAF (BRAF(V600E)) depend on RAF–MEK–ERK signalling for tumour cell growth1. RAF and MEK inhibitors show remarkable clinical efficacy in BRAF(V600E) melanoma2, 3; however, resistance to these agents remains a formidable challenge2, 4. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here we carried out systematic gain-of-function resistance studies by expressing more than 15,500 genes individually in a BRAF(V600E) melanoma cell line treated with RAF, MEK, ERK or combined RAF–MEK inhibitors. These studies revealed a cyclic-AMP-dependent melanocytic signalling 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 BRAF(V600E) melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF–MEK inhibition but restored in relapsing tumours. 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 MAPK-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 signalling- and chromatin-directed therapeutics.