在日前在線出版的《自然—化學(xué)生物學(xué)》上發(fā)表了一項(xiàng)研究成果稱,，研究人員發(fā)現(xiàn)了癌癥治療中導(dǎo)致PI3激酶（PI3K）抑制劑抗藥性的機(jī)制，這將有助于科學(xué)家們在這種抗藥性出現(xiàn)之前開發(fā)出對付它的新戰(zhàn)略,，同時(shí)提高患者的治療效果。
在超過25%的乳腺癌患者體內(nèi),，負(fù)責(zé)編碼PI3K的基因發(fā)生了變異,，促進(jìn)了乳腺惡性腫瘤的生長。PI3K抑制劑的開發(fā)已經(jīng)到了臨床試驗(yàn)階段,，然而,，盡管這種治療方法充滿前景，但針對目標(biāo)治療的抗藥性經(jīng)常出現(xiàn),。
Sebastian Nijman和同事用一種化學(xué)遺傳學(xué)方法,，預(yù)料乳腺癌細(xì)胞中NOTCH1通道和c-MYC基因的活性能對PI3K抑制劑形成抗性。以前的研究并沒有將NOTCH1通道與乳腺癌聯(lián)系在一起,。作者相信,，通過認(rèn)識(shí)治療過程中腫瘤上所發(fā)生的變化類型，科學(xué)家們能夠在PI3K抑制劑抗藥性形成之前開發(fā)更好的方法來對付它,。(生物谷 Bioon.com)
doi:10.1038/nchembio.695
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A chemical-genetic screen reveals a mechanism of resistance to PI3K inhibitors in cancer
Markus K Muellner, Iris Z Uras,, Bianca V Gapp,, Claudia Kerzendorfer, Michal Smida, Hannelore Lechtermann, Nils Craig-Mueller, Jacques Colinge, Gerhard Duernberger & Sebastian M B Nijman
Linking the molecular aberrations of cancer to drug responses could guide treatment choice and identify new therapeutic applications. However, there has been no systematic approach for analyzing gene-drug interactions in human cells. Here we establish a multiplexed assay to study the cellular fitness of a panel of engineered isogenic cancer cells in response to a collection of drugs, enabling the systematic analysis of thousands of gene-drug interactions. Applying this approach to breast cancer revealed various synthetic-lethal interactions and drug-resistance mechanisms, some of which were known, thereby validating the method. NOTCH pathway activation, which occurs frequently in breast cancer, unexpectedly conferred resistance to phosphoinositide 3-kinase (PI3K) inhibitors, which are currently undergoing clinical trials in breast cancer patients. NOTCH1 and downstream induction of c-MYC over-rode the dependency of cells on the PI3K-mTOR pathway for proliferation. These data reveal a new mechanism of resistance to PI3K inhibitors with direct clinical implications.
