Glioblastoma (GBM) is a highly aggressive and lethal
brain cancer type. PI3K and MAPK inhibitors have been studied preclinically in GBM as monotherapy, but not in combination with
radiotherapy, which is a key component of the current standard treatment of GBM. In our study, GBM cell lines and patient representative primary cultures were grown as multicellular spheroids. Spheroids were treated with a panel of small-molecule drugs including
MK2206,
RAD001,
BEZ235,
MLN0128, and
MEK162, alone and in combination with irradiation. Following treatment, spheroid growth parameters (growth rate, volume reduction, and time to regrow), cell-cycle distribution and expression of key target
proteins were evaluated. In vivo, the effect of irradiation (3 × 2 Gy) without or with
MEK162 (50 mg/kg) was studied in orthotopic GBM8
brain tumor xenografts with endpoints
tumor growth and animal survival. The MAPK-targeting agent
MEK162 was found to enhance the effect of irradiation as demonstrated by growth inhibition of spheroids.
MEK162 downregulated and dephosphorylated the cell-cycle checkpoint
proteins CDK1/CDK2/WEE1 and DNA damage response
proteins p-ATM/p-CHK2. When combined with radiation, this led to a prolonged DNA damage signal. In vivo data on
tumor-bearing animals demonstrated a significantly reduced growth rate, increased growth delay, and prolonged survival time. In addition,
RNA expression of responsive cell cultures correlated to mesenchymal stratification of patient expression data. In conclusion, the MAPK inhibitor
MEK162 was identified as a radiosensitizer in GBM spheroids in vitro and in orthotopic GBM xenografts in vivo The data are supportive for implementation of this targeted agent in an early-phase clinical study in GBM patients. Mol
Cancer Ther; 17(2); 347-54. ©2017 AACRSee all articles in this MCT Focus section, "Developmental
Therapeutics in Radiation Oncology."