Radiosensitizing effect of MEK-inhibition in glioblastoma in vitro and in vivo

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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 significantly better survival compared to vehicle (both P<0.005), however, no significant 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.

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