酪氨酸激酶抑制劑(tyrosine kinase inhibitors, TKIs)通過誘導(dǎo)程序性細胞死亡而殺死癌細胞,。它們給患有慢性骨髓白血病(chronic myeloid leukemia, CML)和某些類型肺癌的病人帶來巨大的治療益處，但是它們的有效地可能在不同個人之間存在差別,。之前的研究已估計TKIs 對大約五分之一的病人沒有療效,。如今,，來自包括 Yijun Ruan、Axel Hillmer,、Sin Tiong Ong,、King Pan Ng、Charles Chuah和Darren Wan-Teck Lim在內(nèi)的一個研究小組鑒定出一種常見性的基因變異與TKIs耐藥性相關(guān)聯(lián),。
Ng、Hillmer和他們的同事們對5名CML病人(其中3人對TKIs產(chǎn)生耐藥性)的基因組進行測序和比較,，并著重關(guān)注已知參與細胞死亡信號通路的幾個候選基因,。研究人員發(fā)現(xiàn)這5名病人都在BIM基因非編碼區(qū)域中第2903堿基對刪除，其中BIM基因編碼細胞死亡基因BCL2蛋白家族中的一個成員,。
他們?nèi)缓髮?500多名健康的個人進行基因組篩選,，發(fā)現(xiàn)這種刪除是一種常見的變異，在將近八分之一的東亞個人體內(nèi)發(fā)生,，但是在非洲人和歐洲人體內(nèi)并沒有發(fā)現(xiàn),。進一步試驗揭示出這種刪除改變對BIM基因轉(zhuǎn)錄產(chǎn)生的mRNA進行的加工。正因為如此,，細胞死亡激活結(jié)構(gòu)域中的編碼序列優(yōu)先被移除,，因此根據(jù)這種轉(zhuǎn)錄本合成出的BIM蛋白是有缺陷的。
最終,，研究人員發(fā)現(xiàn)啊BIM基因上的這種刪除是一種有用的生物標(biāo)記物,，可以被用來預(yù)測哪些病人有風(fēng)險對TKIs產(chǎn)生耐藥性,。他們研究了203名東亞癌癥病人對藥物伊馬替尼(imatinib)的反應(yīng)，結(jié)果發(fā)現(xiàn)發(fā)生這種刪除突變的CML病人更加可能對它產(chǎn)生耐藥性,。
在肺癌病人體內(nèi),，這種刪除與藥物反應(yīng)的持續(xù)時間相關(guān)聯(lián)，并且能夠被用來預(yù)測病人在沒有疾病惡化時擁有更短的存活時間,。攜帶這種刪除突變的那些病人的平均無疾病惡化存活期限為大約6個半月時間,，而沒有這種突變的那些病人則為將近12個月。(生物谷：Bioon.com)
本文編譯自A genetic variation common in East Asian populations has been linked to cancer drug resistance
doi: 10.1038/nm.2713
PMC:
PMID:
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.
