ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology

J Cell Mol Med. 2021 Nov;25(22):10591-10603. doi: 10.1111/jcmm.16990. Epub 2021 Oct 16.


Sorafenib is a multikinase inhibitor widely used in cancer therapy with an antitumour effect related to biological processes as proliferation, migration or invasion, among others. Initially designed as a Raf inhibitor, Sorafenib was later shown to also block key molecules in tumour progression such as VEGFR and PDGFR. In addition, sorafenib has been connected with key signalling pathways in cancer such as EGFR/EGF. However, no definitive clue about the molecular mechanism linking sorafenib and EGF signalling pathway has been established so far. Our data in HeLa, U2OS, A549 and HEK293T cells, based on in silico, chemical and genetic approaches demonstrate that the MEK5/ERK5 signalling pathway is a novel target of sorafenib. In addition, our data show how sorafenib is able to block MEK5-dependent phosphorylation of ERK5 in the Ser218/Tyr220, affecting the transcriptional activation associated with ERK5. Moreover, we demonstrate that some of the effects of this kinase inhibitor onto EGF biological responses, such as progression through cell cycle or migration, are mediated through the effect exerted onto ERK5 signalling pathway. Therefore, our observations describe a novel target of sorafenib, the ERK5 signalling pathway, and establish new mechanistic insights for the antitumour effect of this multikinase inhibitor.

Keywords: EGF; ERK5; MEK5; Sorafenib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Movement
  • Disease Susceptibility
  • Epidermal Growth Factor / metabolism
  • Flow Cytometry
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • Mitogen-Activated Protein Kinase 7 / chemistry
  • Mitogen-Activated Protein Kinase 7 / metabolism*
  • Molecular Targeted Therapy
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Signal Transduction / drug effects
  • Sorafenib / chemistry
  • Sorafenib / pharmacology*
  • Structure-Activity Relationship


  • Biomarkers, Tumor
  • Protein Kinase Inhibitors
  • Epidermal Growth Factor
  • Sorafenib
  • MAPK7 protein, human
  • Mitogen-Activated Protein Kinase 7