在日前在线出版的《自然—化学生物学》上发表了一项研究成果称，研究人员发现了癌症治疗中导致PI3激酶（PI3K）抑制剂抗药性的机制，这将有助于科学家们在这种抗药性出现之前开发出对付它的新战略，同时提高患者的治疗效果。
在超过25%的乳腺癌患者体内，负责编码PI3K的基因发生了变异，促进了乳腺恶性肿瘤的生长。PI3K抑制剂的开发已经到了临床试验阶段，然而，尽管这种治疗方法充满前景，但针对目标治疗的抗药性经常出现。
Sebastian Nijman和同事用一种化学遗传学方法，预料乳腺癌细胞中NOTCH1通道和c-MYC基因的活性能对PI3K抑制剂形成抗性。以前的研究并没有将NOTCH1通道与乳腺癌联系在一起。作者相信，通过认识治疗过程中肿瘤上所发生的变化类型，科学家们能够在PI3K抑制剂抗药性形成之前开发更好的方法来对付它。(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.
