TY - JOUR
T1 - Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma
AU - Dasgupta, Tina
AU - Olow, Aleksandra K.
AU - Yang, Xiaodong
AU - Hashizume, Rintaro
AU - Nicolaides, Theodore P.
AU - Tom, Maxwell
AU - Aoki, Yasuyuki
AU - Berger, Mitchel S.
AU - Weiss, William A.
AU - Stalpers, Lukas J.A.
AU - Prados, Michael
AU - David James, C.
AU - Mueller, Sabine
AU - Haas-Kogan, Daphne A.
N1 - Publisher Copyright:
© 2016, Springer Science+Business Media New York.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - Radiation (RT) is critical to the treatment of high-grade gliomas (HGGs) but cures remain elusive. The BRAF mutation V600E is critical to the pathogenesis of 10–20 % of pediatric gliomas, and a small proportion of adult HGGs. Here we aim to determine whether PLX4720, a specific BRAF V600E inhibitor, enhances the activity of RT in human HGGs in vitro and in vivo. Patient-derived HGG lines harboring wild-type BRAF or BRAF V600E were assessed in vitro to determine IC50 values, cell cycle arrest, apoptosis and senescence and elucidate mechanisms of combinatorial activity. A BRAF V600E HGG intracranial xenograft mouse model was used to evaluate in vivo combinatorial efficacy of PLX4720+RT. Tumors were harvested for immunohistochemistry to quantify cell cycle arrest and apoptosis. RT+PLX4720 exhibited greater anti-tumor effects than either monotherapy in BRAF V600E but not in BRAF WT lines. In vitro studies showed increased Annexin V and decreased S phase cells in BRAF V600E gliomas treated with PLX4720+RT, but no significant changes in β-galactosidase levels. In vivo, concurrent and sequential PLX4720+RT each significantly prolonged survival compared to monotherapies, in the BRAF V600E HGG model. Immunohistochemistry of in vivo tumors demonstrated that PLX4720+RT decreased Ki-67 and phospho-MAPK, and increased γH2AX and p21 compared to control mice. BRAF V600E inhibition enhances radiation-induced cytotoxicity in BRAF V600E-mutated HGGs, in vitro and in vivo, effects likely mediated by apoptosis and cell cycle, but not senescence. These studies provide the pre-clinical rationale for clinical trials of concurrent radiotherapy and BRAF V600E inhibitors.
AB - Radiation (RT) is critical to the treatment of high-grade gliomas (HGGs) but cures remain elusive. The BRAF mutation V600E is critical to the pathogenesis of 10–20 % of pediatric gliomas, and a small proportion of adult HGGs. Here we aim to determine whether PLX4720, a specific BRAF V600E inhibitor, enhances the activity of RT in human HGGs in vitro and in vivo. Patient-derived HGG lines harboring wild-type BRAF or BRAF V600E were assessed in vitro to determine IC50 values, cell cycle arrest, apoptosis and senescence and elucidate mechanisms of combinatorial activity. A BRAF V600E HGG intracranial xenograft mouse model was used to evaluate in vivo combinatorial efficacy of PLX4720+RT. Tumors were harvested for immunohistochemistry to quantify cell cycle arrest and apoptosis. RT+PLX4720 exhibited greater anti-tumor effects than either monotherapy in BRAF V600E but not in BRAF WT lines. In vitro studies showed increased Annexin V and decreased S phase cells in BRAF V600E gliomas treated with PLX4720+RT, but no significant changes in β-galactosidase levels. In vivo, concurrent and sequential PLX4720+RT each significantly prolonged survival compared to monotherapies, in the BRAF V600E HGG model. Immunohistochemistry of in vivo tumors demonstrated that PLX4720+RT decreased Ki-67 and phospho-MAPK, and increased γH2AX and p21 compared to control mice. BRAF V600E inhibition enhances radiation-induced cytotoxicity in BRAF V600E-mutated HGGs, in vitro and in vivo, effects likely mediated by apoptosis and cell cycle, but not senescence. These studies provide the pre-clinical rationale for clinical trials of concurrent radiotherapy and BRAF V600E inhibitors.
KW - BRAF V600E
KW - High-grade gliomas
KW - Radiotherapy
KW - Targeted inhibitors
UR - http://www.scopus.com/inward/record.url?scp=84956638735&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84956638735&partnerID=8YFLogxK
U2 - 10.1007/s11060-015-1939-2
DO - 10.1007/s11060-015-1939-2
M3 - Article
C2 - 26384810
AN - SCOPUS:84956638735
SN - 0167-594X
VL - 126
SP - 385
EP - 393
JO - Journal of Neuro-Oncology
JF - Journal of Neuro-Oncology
IS - 3
ER -