PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis
PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis
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DOI：
10.1073/pnas.1108237108
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发表时间：
2011-09-13
影响因子：
11.1
通讯作者：
Roberts, Thomas M.
中科院分区：
文献类型：
--
作者：
Ilic, Nina;Utermark, Tamara;Roberts, Thomas M.
PI 3 K通路在癌症中经常被激活;因此，相当大的努力集中在鉴定可以抑制特定通路组分的化合物，特别是标志性致癌基因PIK 3CA。尽管靶向抑制癌症存活基因具有重要的前景，但人们担心癌细胞内可能出现耐药性，从而限制了临床疗效。使用遗传定义的人乳腺上皮细胞，我们进化出对PI 3 K/哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂BEZ 235的抗性，并通过全基因组拷贝数分析，我们鉴定了抗性细胞内的MYC和eIF 4 E扩增。重要的是，MYC或真核翻译起始因子4 E（eIF 4 E）需要绕过抗性细胞中的药理学PI 3 K/mTOR抑制。此外，这些细胞显示升高的5'帽依赖性蛋白质翻译。总的来说，这些发现表明，对蛋白质翻译驱动因素的分析可以促进对PI 3 K通路靶向药物产生耐药性的癌症病变的鉴定。
The PI3K pathway is frequently activated in cancer; therefore, considerable effort is focused on identifying compounds that can inhibit specific pathway components, particularly the hallmark oncogene PIK3CA. Although targeted inhibition of a cancer survival gene holds significant promise, there are concerns that drug resistance may emerge within the cancerous cells, thus limiting clinical efficacy. Using genetically defined human mammary epithelial cells, we evolved resistance to the PI3K/mammalian target of rapamycin (mTOR) inhibitor BEZ235, and by genome-wide copy number analyses, we identified MYC and eIF4E amplification within the resistant cells. Importantly, either MYC or eukaryotic translation initiation factor 4E (eIF4E) was required to bypass pharmacological PI3K/mTOR inhibition in resistant cells. Furthermore, these cells displayed elevated 5' cap-dependent protein translation. Collectively, these findings suggest that analysis of drivers of protein translation could facilitate the identification of cancer lesions that confer resistance to PI3K pathway-targeted drugs.