Nature:科学家开发出研究癌症药物抗性的新方法

 

   

 近期发表在Nature杂志上的文章称,科学家开发出一种新型研究癌症药物抗性的方法。该方法有助于确定黑色素瘤产生的信号通路以及开发抗癌疗法。

 

 

    在黑色素瘤中,有50%病人是有BRAF基因突变,几年前,科学家开发出破坏该信号通路的药物,该药物效果非常显著,但是仅仅维持了九个月。Garraway博士希望找到肿瘤产生药物抗性的原因。

 

     科学家采用开放阅读框(Open Reading Frame,ORF)文库的方式在BRAF突变的黑色素瘤细胞中逐个的激活一万五千个基因。该系统性研究方法揭示了黑色素瘤产生药物抗性的基因图谱。

 

    该研究最关键也是最惊人的发现是找到了BRAF突变黑色素瘤产生药物抗性的关键信号通路。该文章的第一作者Johannessen博士称,这就证明了药物抗性的产生并不是随机事件,是维持表皮细胞持续生长的信号通路起关键作用。

 

    该文章的通讯作者Garraway博士称,该方法能够更系统的研究药物抗性的机制问题,我们确定了癌症的抗药机制才能进一步的开发针对该机制的治疗方法。我们希望多种药物结合的方法能够更有效,更持久的治疗癌症。

 

 

 

 
   
A melanocyte lineage program confers resistance to MAP kinase pathway inhibition
 
Cory M. Johannessen,     Laura A. Johnson, Federica Piccioni,   Aisha Townes,        Dennie T. Frederick,       Melanie K. Donahue,         Rajiv Narayan,        Keith T. Flaherty,    Jennifer A. Wargo,         David E. Root          & Levi A. Garraway
 
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) melanoma23; however, resistance to these agents remains a formidable challenge24. 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-FOSNR4A1NR4A2 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.