MAPK kinase signalling dynamics regulate cell fate decisions and drug resistance
MAPK kinase signalling dynamics regulate cell fate decisions and drug resistance
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DOI：
10.1016/j.sbi.2016.07.019
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发表时间：
2016-12-01
影响因子：
6.8
通讯作者：
Kholodenko, Boris N.
中科院分区：
文献类型：
--
作者：
Rauch, Nora;Rukhlenko, Oleksii S.;Kholodenko, Boris N.
RAS/RAF/MEK/MAPK 激酶通路已被广泛研究超过 25 年，但我们仍然对其复杂的动态控制和可塑性感到困惑。不同的时空 MAPK 动态导致正常细胞与癌细胞和发育中生物体的不同细胞命运决定。最近的建模和实验研究为由大量前馈/反馈调节和多个时间尺度上的串扰协调的多功能 MAPK 动力学提供了新颖的见解。多种癌症类型和各种发育障碍是由 RAS/RAF/MEK 突变引起的 MAPK 动态的持续改变引起的。虽然MAPK通路在多种疾病中的关键作用使得新型RAF/MEK抑制剂的开发成为药物开发的热点，但这些药物具有意想不到的副作用，不可避免地会出现耐药性。我们回顾了 RAF 二聚化如何传递耐药性以及克服这种耐药性的最新突破。
The RAS/RAF/MEK/MAPK kinase pathway has been extensively studied for more than 25 years, yet we continue to be puzzled by its intricate dynamic control and plasticity. Different spatiotemporal MAPK dynamics bring about distinct cell fate decisions in normal vs cancer cells and developing organisms. Recent modelling and experimental studies provided novel insights in the versatile MAPK dynamics concerted by a plethora of feedforward/feedback regulations and crosstalk on multiple timescales. Multiple cancer types and various developmental disorders arise from persistent alterations of the MAPK dynamics caused by RAS/RAF/MEK mutations. While a key role of the MAPK pathway in multiple diseases made the development of novel RAF/MEK inhibitors a hot topic of drug development, these drugs have unexpected side-effects and resistance inevitably occurs. We review how RAF dimerization conveys drug resistance and recent breakthroughs to overcome this resistance.