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

Abstract

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.

A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma

“…Interestingly, all those pathways have been shown to activate ERK5. In breast cancer, ERK5 contributes to the response to EGF stimulation [ 55 ] and is involved in the resistance to ErbB-2 (HER2) inhibitors by facilitating G1-S transition [ 56 ]. In BRAF mutant melanoma resistant to BRAFi and MEKi, IGF1R activation induces ERK5 phosphorylation [ 57 ].…”

ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology

“…Protein quantification and western blot were performed as previously described [ 29 ]. For tumor samples, 400 μL of lysis buffer was added to 0.2 g of tumor, and it was disaggregated using a Polytron PT-2100 (Kinematica AG, Malters, Switzerland).…”

The role of angiogenesis in melanoma: Clinical treatments and future expectations

“…Sorafenib is a raf kinase inhibitor, which can also inhibit the tyrosine kinase activity of various receptors, including VGFR-2, VEGF-3, PDGF-β, KIT, FLT-3, and other receptors. Sorafenib has dual anti-tumor effects ( Ortega-Muelas et al, 2021 ), which can not only directly inhibit the proliferation of tumor cells by mediating RAF/MEK/ERK pathway but also cut off the nutrition of tumor cells through inhibiting the formation of new blood vessels ( Spirli et al, 2012 ). To evaluate the safety, effectiveness, health-related quality of life (HRQoL), and the non-progression rate of Sorafenib (800 mg per day), a multicenter, single-arm phase II trial was conducted in patients with metastatic uveal melanoma.…”