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MAPK kinase signalling dynamics regulate cell fate decisions and drug resistance

Curr Opin Struct Biol. 2016 Dec:41:151-158. doi: 10.1016/j.sbi.2016.07.019. Epub 2016 Aug 10.

Abstract

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.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / drug effects
  • Drug Resistance, Neoplasm*
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • Mitogen-Activated Protein Kinases / chemistry
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neoplasms / drug therapy
  • Neoplasms / pathology*
  • Protein Multimerization / drug effects

Substances

  • Mitogen-Activated Protein Kinases