Synergistic effects of eIF4A and MEK inhibitors on proliferation of NRAS-mutant melanoma cell lines - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Cell Cycle Année : 2016

Synergistic effects of eIF4A and MEK inhibitors on proliferation of NRAS-mutant melanoma cell lines

Qian Zhao
  • Fonction : Auteur
  • PersonId : 1069352
Laurent Désaubry

Résumé

Activating mutations of the NRAS (neuroblastoma rat sarcoma viral oncogene) protein kinase, present in many cancers, induce a constitutive activation of both the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal transduction pathway and the PI(3)K-AKT-mTOR, pathway. This in turn regulates the formation of the eIF4F eukaryotic translation initiation complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, which binds to the 7-methylguanylate cap (m(7)G) at the 5' end of messenger RNAs. Small molecules targeting MEK (MEKi: MEK inhibitors) have demonstrated activity in NRAS-mutant cell lines and tumors, but resistance sets in most cases within months of treatment. Using proximity ligation assays, that allows visualization of the binding of eIF4E to the scaffold protein eIF4G, generating the active eIF4F complex, we have found that resistance to MEKi is associated with the persistent formation of the eIF4F complex in MEKi-treated NRAS-mutant cell lines. Furthermore, inhibiting the eIF4A component of the eIF4F complex, with a small molecule of the flavagline/rocaglate family, synergizes with inhibiting MEK to kill NRAS-mutant cancer cell lines.

Domaines

Cancer

Dates et versions

hal-03536458 , version 1 (19-01-2022)

Identifiants

Citer

Hélène Malka-Mahieu, Isabelle Girault, Margot Rubington, Melissa Leriche, Caroline Welsch, et al.. Synergistic effects of eIF4A and MEK inhibitors on proliferation of NRAS-mutant melanoma cell lines. Cell Cycle, 2016, 15 (18), pp.2405-2409. ⟨10.1080/15384101.2016.1208862⟩. ⟨hal-03536458⟩
37 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More