BRAF Status in Personalizing Treatment Approaches for Pediatric Gliomas

• Published in: Clinical cancer research Vol. 22; no. 21; pp. 5312 - 5321
• Main Authors: Olow, Aleksandra, Mueller, Sabine, Yang, Xiaodong, Hashizume, Rintaro, Meyerowitz, Justin, Weiss, William, Resnick, Adam C, Waanders, Angela J, Stalpers, Lukas J A, Berger, Mitchel S, Gupta, Nalin, James, C David, Petritsch, Claudia K, Haas-Kogan, Daphne A
• Format: Journal Article
• Language: English
• Published: United States 01.11.2016
• Subjects: Animals; Antineoplastic Agents - pharmacology; Benzimidazoles - pharmacology; Cell Line; Cell Line, Tumor; Cell Survival - drug effects; Glioma - drug therapy; Glioma - metabolism; Humans; Indoles - pharmacology; MAP Kinase Kinase 1 - metabolism; MAP Kinase Kinase 2 - metabolism; Mice; NIH 3T3 Cells; Proto-Oncogene Proteins B-raf - metabolism; S Phase - drug effects; Sulfonamides - pharmacology; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-15-1101

Alteration of the BRAF/MEK/MAPK pathway is the hallmark of pediatric low-grade gliomas (PLGGs), and mTOR activation has been documented in the majority of these tumors. We investigated combinations of MEK1/2, BRAF and mTOR inhibitors in gliomas carrying specific genetic alterations of the MAPK pathway. We used human glioma lines containing BRAF (adult high-grade: AM-38, DBTRG, PLGG: BT40), or wild-type BRAF (pediatric high-grade: SF188, SF9427, SF8628) and isogenic systems of KIAA1549:BRAF-expressing NIH/3T3 cells and BRAF -expressing murine brain cells. Signaling inhibitors included everolimus (mTOR), PLX4720 (BRAF ), and AZD6244 (MEK1/2). Proliferation was determined using ATP-based assays. In vivo inhibitor activities were assessed in the BT40 PLGG xenograft model. In BRAF cells, the three possible doublet combinations of AZD6244, everolimus, and PLX4720 exhibited significantly greater effects on cell viability. In BRAF cells, everolimus + AZD6244 was superior compared with respective monotherapies. Similar results were found using isogenic murine cells. In KIAA1549:BRAF cells, MEK1/2 inhibition reduced cell viability and S-phase content, effects that were modestly augmented by mTOR inhibition. In vivo experiments in the BRAF pediatric xenograft model BT40 showed the greatest survival advantage in mice treated with AZD6244 + PLX4720 (P < 0.01). In BRAF tumors, combination of AZD6244 + PLX4720 is superior to monotherapy and to other combinatorial approaches. In BRAF pediatric gliomas, everolimus + AZD6244 is superior to either agent alone. KIAA1549:BRAF-expressing tumors display marked sensitivity to MEK1/2 inhibition. Application of these results to PLGG treatment must be exercised with caution because the dearth of PLGG models necessitated only a single patient-derived PLGG (BT40) in this study. Clin Cancer Res; 22(21); 5312-21. ©2016 AACR.