TY - JOUR
T1 - Identification of MEK162 as a Radiosensitizer for the Treatment of Glioblastoma
AU - Narayan, Ravi S.
AU - Gasol, Ana
AU - Slangen, Paul L. G.
AU - Cornelissen, Fleur M. G.
AU - Lagerweij, Tonny
AU - Veldman, Hou Y. Y. E.
AU - Dik, Rogier
AU - van den Berg, Jaap
AU - Slotman, Ben J.
AU - Wurdinger, Tom
AU - Haas-Kogan, Daphne A.
AU - Stalpers, Lukas J. A.
AU - Baumert, Brigitta G.
AU - Westerman, Bart A.
AU - Theys, Jan
AU - Sminia, Peter
PY - 2018/2/1
Y1 - 2018/2/1
N2 - Glioblastoma (GBM) is a highly aggressive and lethal brain cancer type. PI3K and MAPK inhibitors have been studied pre-clinically 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 x 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. (C) 2017 AACR.
AB - Glioblastoma (GBM) is a highly aggressive and lethal brain cancer type. PI3K and MAPK inhibitors have been studied pre-clinically 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 x 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. (C) 2017 AACR.
KW - ADJUVANT TEMOZOLOMIDE
KW - MICHAELIS-MENTEN
KW - KINETIC SYSTEMS
KW - CELL-SURVIVAL
KW - OPEN-LABEL
KW - CANCER
KW - INHIBITORS
KW - RADIATION
KW - RADIOTHERAPY
KW - EGFR
U2 - 10.1158/1535-7163.MCT-17-0480
DO - 10.1158/1535-7163.MCT-17-0480
M3 - Article
C2 - 28958992
SN - 1535-7163
VL - 17
SP - 347
EP - 354
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 2
ER -