近日,，一項刊登在PNAS雜志上的最近研究發(fā)現(xiàn),，一種廉價的治療睡眠障礙的藥物似乎也是一種癌細(xì)胞的強效抑制劑,。Fred Hutchinson癌癥研究中心的研究人員通過迅速分析基因組后發(fā)現(xiàn)了這一藥物的作用靶點，研究人員表示這項研究對更有效和更安全的治療癌癥的發(fā)展具有深遠(yuǎn)的影響,。
研究主要領(lǐng)導(dǎo)者——Carla Grandori醫(yī)學(xué)博士使用高通量篩選技術(shù)結(jié)合siRNA基因沉默技術(shù)發(fā)現(xiàn)了癌細(xì)胞的致命弱點,，這一致命弱點是由Myc基因驅(qū)動的。
幸運的是,，Myc驅(qū)動癌細(xì)胞有一個致命的弱點,。其快速生長和分裂會破壞它們的DNA，腫瘤細(xì)胞依賴于其他基因修復(fù)損害,。一旦抑制這些基因可以就削弱癌細(xì)胞的能增長力。
Grandori和他的團隊發(fā)現(xiàn)了超過100個基因能殺死Myc驅(qū)動的癌細(xì)胞,，而不影響正常細(xì)胞,，這意味著這些基因可能是一個新的、無毒的癌癥治療的靶標(biāo),。
其中一個特別有前途的基因就是CSNK 1,，該基因在殺死癌細(xì)胞的同時并不影響正常組織，而且已經(jīng)有該基因的抑制劑誕生,，該抑制劑是一種化合物,，最初開發(fā)用來調(diào)節(jié)睡眠周期的。
高通量篩選技術(shù)結(jié)合siRNA沉默技術(shù),，Grandori表示：癌癥治療方可能會出現(xiàn)一個根本性的轉(zhuǎn)變,。（生物谷：Bioon.com）
doi:10.1073/pnas.1121119109
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Functional genomics identifies therapeutic targets for MYC-driven cancer
Masafumi Toyoshima, Heather L. Howie, Maki Imakura, Ryan M. Walsh, James E. Annis, Aaron N. Chang, Jason Frazier, B. Nelson Chau, Andrey Loboda, Peter S. Linsley, Michele A. Cleary, Julie R. Park, and Carla Grandori
MYC oncogene family members are broadly implicated in human cancers, yet are considered “undruggable” as they encode transcription factors. MYC also carries out essential functions in proliferative tissues, suggesting that its inhibition could cause severe side effects. We elected to identify synthetic lethal interactions with c-MYC overexpression (MYC-SL) in a collection of ∼3,300 druggable genes, using high-throughput siRNA screening. Of 49 genes selected for follow-up, 48 were confirmed by independent retesting and approximately one-third selectively induced accumulation of DNA damage, consistent with enrichment in DNA-repair genes by functional annotation. In addition, genes involved in histone acetylation and transcriptional elongation, such as TRRAP and BRD4, were identified, indicating that the screen revealed known MYC-associated pathways. For in vivo validation we selected CSNK1e, a kinase whose expression correlated with MYCN amplification in neuroblastoma (an established MYC-driven cancer). Using RNAi and available small-molecule inhibitors, we confirmed that inhibition of CSNK1e halted growth of MYCN-amplified neuroblastoma xenografts. CSNK1e had previously been implicated in the regulation of developmental pathways and circadian rhythms, whereas our data provide a previously unknown link with oncogenic MYC. Furthermore, expression of CSNK1e correlated with c-MYC and its transcriptional signature in other human cancers, indicating potential broad therapeutic implications of targeting CSNK1e function. In summary, through a functional genomics approach, pathways essential in the context of oncogenic MYC but not to normal cells were identified, thus revealing a rich therapeutic space linked to a previously “undruggable” oncogene.
