Radio-sensitizing effect of MEK inhibition in glioblastoma in vitro and in vivo

Abstract

Glioblastoma (GBM) is an incurable cancer type. New therapeutic options are investigated, including targeting the mitogen-activated protein kinase (MAPK) pathway using MEK-inhibitors as radiosensitizers.In this study, we investigated whether MEK-inhibition via PD0325901 leads to radiosensitization in experimental in vitro and in vivo models of GBM. In vitro, GBM8 multicellular spheroids were irradiated with 3 fractions of 2 Gy, during 5 consecutive days of incubation with either PD0325901 or MEK-162.Regrowth and viability of spheroids monitored until day 18, showed that both MEK-inhibitors had an in vitro radiosensitizing effect. In vivo, PD0325901 concentrations were relatively constant throughout multiple brain areas. We combined PD0325901 with radiotherapy in the GBM8 orthotopic mouse model.Tumor growth was measured weekly by bioluminescence imaging and overall survival and toxicity were assessed, showing temporal PD0325901-related adverse events such as dermatitis in 4 out of 14 mice (29%). Mice that were treated with radiation alone or combined with PD0325901 had signi cantly better survival compared to vehicle (both P<0.005), however, no signi cant interaction between PD0325901 MEK-inhibition and irradiation was observed. The difference between the radiotherapy-enhancing effect of PD0325901 in vitro and in vivo urges further pharmacodynamic/pharmacokinetic investigation of PD0325901 and possibly other candidate MEK inhibitors.

KRAS is a molecular determinant of platinum responsiveness in glioblastoma

“…The dysfunctional signalling in tumours arises also by rewiring of signalling pathways, also determining the response to treatment. KRAS signalling necessarily relies on ERK/MEK signalling and, MEK-inhibitors as single agent or in combinatorial setting are at the leading-edge treatment for many cancers, including glioblastoma [ 19 ]. Actually, clinically approved MEK inhibitors (i.e.Trametinib) showed no apparent benefit of blocking MEK [ 35 ].…”

“…Within the area of combinatorial therapies, MEK inhibitors have currently growing advances in clinical trial in glioblastoma treatment [ 19 ]. PD98059, a potent but reversible MEK inhibitor, has recently developed as a new formulation to obtain long-term inhibition of pERK1/2 in brain regions at detectable levels [ 30 ].…”

Small Molecule Tyrosine Kinase Inhibitors (TKIs) for Glioblastoma Treatment

“…According to Houweling et al [169], mirdametinib showed an in vitro radio sensitizing effect on GBM8 spheroids. Mice treated with radiation alone or combined with mirdametinib exhibited significantly better survival if compared to control.…”