Purpose:Malignant astrocytomas (MAs) are aggressive central nervous system tumors with poor prognosis. Activating mutation of BRAF (BRAFV600E) has been reported in a subset of these tumors, especially in children. We have investigated the incidence of BRAFV600E in additional pediatric patient cohorts, and examined the effects of BRAF blockade in preclinical models of BRAFV600E and wild-type BRAF MA. Experimental Design:BRAFV600E mutation status was examined in two pediatric MA patient cohorts. For functional studies, BRAFV600E MA cell lines were used to investigate the effects of BRAF shRNA knockdown in vitro, and to investigate BRAF pharmacologic inhibition, in vitro and in vivo. Results:BRAFV600E mutations were identified in 11 and 10 percent of MAs from two distinct series of tumors (6 of 58 cases total). BRAF was expressed in all MA cell lines examined, among which BRAFV600E was identified in four instances. Using the BRAFV600E specific inhibitor PLX4720, pharmacologic blockade of BRAF revealed preferential anti-proliferative activity against BRAFV600E mutant cells in vitro, in contrast to the use of shRNA-mediated knockdown of BRAF, which inhibited cell growth of glioma cell lines regardless of BRAF mutation status. Using orthotopic MA xenografts, we demonstrate that PLX4720 treatment decreases tumor growth and increases overall survival in mice bearing BRAFV600E mutant xenografts, while being ineffective, and possibly tumor promoting, against xenografts with wild-type BRAF. Conclusions:Our results indicate a 10% incidence of activating BRAFV600E among pediatric MAs. With regard to implications for therapy, our results support evaluation of BRAFV600E specific inhibitors for treating BRAFV600E MA patients.
- Received June 13, 2011.
- Revision received October 14, 2011.
- Accepted October 19, 2011.
- Copyright © 2011, American Association for Cancer Research.