MEK inhibitor for gastric cancer with MEK1 gene mutations
Menée in vitro, in vivo et à l'aide de 46 échantillons tumoraux prélevés sur des patients atteints d'un cancer de l'estomac, cette étude suggère l'intérêt des inhibiteurs de MEK pour le traitement des patients dont les tumeurs présentent des mutations du gène MEK1
The prognosis for patients with unresectable advanced or recurrent gastric cancer (GC) remains poor. The identification of additional oncogenes with influences similar to those of epidermal growth factor receptor gene mutations and upon which the growth of cancer cells is dependent is needed. In this study, we evaluated the sensitivity to MEK inhibitors (GSK1120212 and PD0325901) in several GC cell lines in vitro and found three poorly differentiated GC cell lines that were hypersensitive to the inhibitors. The sequence analyses in these three cell lines revealed that one cell line had a novel MEK1 mutation, while the other two had previously reported KRAS and MEK1 mutations, respectively; the gene statuses of the other resistant cell lines were all wild-type. Experiments using MEK1 expression vectors demonstrated that the MEK1 mutations induced the phosphorylation of ERK1/2 and had a transforming potential, enhancing the tumorigenicity. The MEK inhibitor dramatically reduced the phosphorylation of ERK1/2 and induced apoptosis in the cell lines with MEK1 mutations. In vivo, tumor growth was also dramatically decreased by an inhibitor. One of the 46 GC clinical samples that were examined had a MEK1 mutation; this tumor had a poorly differentiated histology. Considering the addiction of cancer cells to active MEK1 mutations for proliferation, GC with such oncogenic MEK1 mutations might be suitable for targeted therapy with MEK inhibitors.
http://mct.aacrjournals.org/content/early/2014/09/24/1535-7163.MCT-14-0429.abstract