Targeting the mitogen­activated protein kinase kinase and protein kinase A pathways overcomes acquired resistance to Selumetinib in low­grade glioma cells.

ABSTRACT

The Ras/Raf/MEK/MAPK signaling cascade is frequently activated in human cancer and serves a crucial role in the oncogenesis of pediatric low­grade gliomas (PLGGs). Therefore, drugs targeting kinases among the mitogen­activated protein kinase (MAPK) effectors of receptor tyrosine kinase signaling may represent promising candidates for the treatment of PLGGs. The aim of the present study was to elucidate the anticancer effects of the MEK inhibitor Selumetinib on two low­grade glioma cell lines and the possible underlying effects on intracellular signal transduction. The two cancer cell lines displayed different levels of sensitivity to Selumetinib, as Res186 cells were resistant (IC50>1 µM), whereas Res259 cells were sensitive (IC50≤1 µM) to MEK inhibition. Despite the different levels of sensitivity, Selumetinib mediated the phosphorylation of AKT and MEK in both cell lines and suppressed the phosphorylated MAPK cascades. In addition, Selumetinib induced cell cycle arrest at the G0/G1 phase by downregulating the expression levels of cyclin D1 and p21 and upregulating those of p27 compared with those in the control cells. A Res259 cell line with acquired resistance to Selumetinib (Res259/R) was next established and biologically and molecularly characterized, and it was demonstrated that addition of a selective cAMP­dependent protein kinase A inhibitor to Selumetinib overcame drug resistance in Res 259/R cells. In conclusion, the results of the present study provided three low­grade glioma cell line models characterized by sensitivity, intrinsic and acquired resistance to Selumetinib, which may be usuful tools to study new mechanisms of chemoresistance to MEK inhibitors and to explore alternative therapeutic strategies in low­grade gliomas for personalization of treatment.