Abstract 940: Differential sensitivity of BRAF mutant glioma cell lines to the new oncogenic BRAF kinase inhibitor UI-152.

Glioblastomas are a highly aggressive and detrimental brain tumor, comprising 50% of all human gliomas. Glioblastomas have a median survival of less than two years after diagnosis because it has a high capacity for proliferation and is extremely chemoresistant. A common molecular event that characterizes glioblastoma is constitutive activation of the RAS-RAF-MAPK signaling pathway. Activating mutation of BRAF (BRAF-V600E) has been reported in a subset of these tumors. We recently developed UI-152 as the new oncogenic BRAF targeting drug. In biochemical assays, UI-152 inhibited BRAF-V600E at very low nanomolar concentrations and showed a 10-fold higher potency against BRAF-V600E than another well-known oncogenic BRAF inhibitor, PLX4032/4720. In the present study, we evaluated the individual IC 50 values of UI-152 from the cell growth inhibitory effects of the six malignant glioma cell lines with different BRAF mutational status. KG-1-C, NMC-G1, and DBTRG-05MG cell lines are heterozygous for BRAF-V600E; A-172, T98G, and U-87MG cell lines are homozygous for wild-type (WT) BRAF. The IC 50 values of UI-152 were determined using crystal violet assays. UI-152 displayed the greatest level of selectivity for BRAF-mutant cells, inhibiting their proliferation more potently than that of cells expressing BRAF-WT. The IC 50 of UI-152 in B-Raf mutant cells was less than 0.2 μM, whereas the IC 50 of cells expressing BRAF-WT were not reached even at 20 μM UI-152. Corresponding immunoblot results showed that UI-152 completely abolished MEK-ERK phosphorylation in DBTRG-05MG cells harboring BRAF-V600E. However, in U-87MG cells expressing BRAF-WT, UI-152 caused the paradoxical activation of the MAPK pathway. UI-152 induced the phosphorylation of MEK/ERK at 5 μM but caused a return to control levels at 10 μM in U-87MG cells. These results indicate that the genetic profile test of glioma is necessary prior to BRAF-targeted therapy to patients. Taken together, our data suggest that UI-152 may be an effective BRAF inhibitor and contribute to a potential therapeutic strategy for brain tumor patients with BRAF mutations. Citation Format: Michael Lee, Jun-Ho Ahn, Soon Kil Ahn, Yong W. Lee. Differential sensitivity of BRAF mutant glioma cell lines to the new oncogenic BRAF kinase inhibitor UI-152. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 940. doi:10.1158/1538-7445.AM2013-940