title: MAPK kinase signalling dynamics regulate cell fate decisions and drug resistance.
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.
authors: Systems Biology Ireland, University College Dublin, Ireland.
authors: Nora
authors: N
authors: Rauch
authors: Systems Biology Ireland, University College Dublin, Ireland.
authors: Oleksii S
authors: OS
authors: Rukhlenko
authors: Systems Biology Ireland, University College Dublin, Ireland; Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Ireland; School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Walter
authors: W
authors: Kolch
authors: Systems Biology Ireland, University College Dublin, Ireland; Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Ireland; School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland. Electronic address: boris.kholodenko@ucd.ie.
authors: Boris N
authors: BN
authors: Kholodenko
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D055503:Protein Multimerization / Q000187:drug effects
chemical_list: D020928:Mitogen-Activated Protein Kinases