酪氨酸激酶抑制剂(tyrosine kinase inhibitors, TKIs)通过诱导程序性细胞死亡而杀死癌细胞。它们给患有慢性骨髓白血病(chronic myeloid leukemia, CML)和某些类型肺癌的病人带来巨大的治疗益处，但是它们的有效地可能在不同个人之间存在差别。之前的研究已估计TKIs 对大约五分之一的病人没有疗效。如今，来自包括 Yijun Ruan、Axel Hillmer、Sin Tiong Ong、King Pan Ng、Charles Chuah和Darren Wan-Teck Lim在内的一个研究小组鉴定出一种常见性的基因变异与TKIs耐药性相关联。
Ng、Hillmer和他们的同事们对5名CML病人(其中3人对TKIs产生耐药性)的基因组进行测序和比较，并着重关注已知参与细胞死亡信号通路的几个候选基因。研究人员发现这5名病人都在BIM基因非编码区域中第2903碱基对删除，其中BIM基因编码细胞死亡基因BCL2蛋白家族中的一个成员。
他们然后对2500多名健康的个人进行基因组筛选，发现这种删除是一种常见的变异，在将近八分之一的东亚个人体内发生，但是在非洲人和欧洲人体内并没有发现。进一步试验揭示出这种删除改变对BIM基因转录产生的mRNA进行的加工。正因为如此，细胞死亡激活结构域中的编码序列优先被移除，因此根据这种转录本合成出的BIM蛋白是有缺陷的。
最终，研究人员发现啊BIM基因上的这种删除是一种有用的生物标记物，可以被用来预测哪些病人有风险对TKIs产生耐药性。他们研究了203名东亚癌症病人对药物伊马替尼(imatinib)的反应，结果发现发生这种删除突变的CML病人更加可能对它产生耐药性。
在肺癌病人体内，这种删除与药物反应的持续时间相关联，并且能够被用来预测病人在没有疾病恶化时拥有更短的存活时间。携带这种删除突变的那些病人的平均无疾病恶化存活期限为大约6个半月时间，而没有这种突变的那些病人则为将近12个月。(生物谷：Bioon.com)
本文编译自A genetic variation common in East Asian populations has been linked to cancer drug resistance
doi: 10.1038/nm.2713
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A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer
King Pan Ng, Axel M Hillmer, Charles T H Chuah et al.
Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor–mutated non–small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be overcome with BH3-mimetic drugs. Notably, individuals with CML and EGFR NSCLC harboring the polymorphism experienced significantly inferior responses to TKIs than did individuals without the polymorphism (P = 0.02 for CML and P = 0.027 for EGFR NSCLC). Our results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism–associated TKI resistance.
