MEK-dependent negative feedback underlies BCR-ABL-mediated oncogene addiction.
MEK-dependent negative feedback underlies BCR-ABL-mediated oncogene addiction.
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DOI：
10.1158/2159-8290.cd-13-0235
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发表时间：
2014-02
期刊：
影响因子：
28.2
通讯作者：
Shah NP
中科院分区：
文献类型：
--
作者：
Asmussen J;Lasater EA;Tajon C;Oses-Prieto J;Jun YW;Taylor BS;Burlingame A;Craik CS;Shah NP
BCR-ABL酪氨酸激酶抑制剂(TKIs)治疗慢性粒细胞白血病(CML)的临床经验为癌基因成瘾提供了令人信服的证据。然而，癌基因成瘾的分子基础仍然难以捉摸。通过对短暂暴露于BCR-ABL TKI的CML细胞的无偏定量磷蛋白组学分析，我们确定了生长因子受体(GF-R)信号通路的持续下调。然后，我们建立并验证了BCR-ABL介导的成瘾的组织相关等基因模型，并发现了髓系GF-R信号通路重新布线的证据，该通路深刻而持久地抑制了生理通路的激活。我们证明，最终恢复配体介导的GF-R途径激活不足以完全将细胞从竞争的凋亡命运中拯救出来。与之前在黑色素瘤细胞中使用BRAFV600E的工作不同，BCR-ABL TKI治疗后的反馈抑制显著延长，超过了启动凋亡所需的时间。从机制上讲，BCR-ABL介导的癌基因成瘾是由持续高水平的MEK依赖的负反馈促进的。
The clinical experience with BCR-ABL tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) provides compelling evidence for oncogene addiction. Yet, the molecular basis of oncogene addiction remains elusive. Through unbiased quantitative phosphoproteomic analyses of CML cells transiently exposed to BCR-ABL TKI, we identified persistent downregulation of growth factor receptor (GF-R) signaling pathways. We then established and validated a tissue-relevant isogenic model of BCR-ABL-mediated addiction, and found evidence for myeloid GF-R signaling pathway rewiring that profoundly and persistently dampens physiologic pathway activation. We demonstrate that eventual restoration of ligand-mediated GF-R pathway activation is insufficient to fully rescue cells from a competing apoptotic fate. In contrast to previous work with BRAFV600E in melanoma cells, feedback inhibition following BCR-ABL TKI treatment is markedly prolonged, extending beyond the time required to initiate apoptosis. Mechanistically, BCR-ABL-mediated oncogene addiction is facilitated by persistent high levels of MEK-dependent negative feedback.