BRAF status in personalizing treatment approaches for pediatric gliomas

Aleksandra Olow, Sabine Mueller, Xiaodong Yang, Rintaro Hashizume, Justin Meyerowitz, William Weiss, Adam C. Resnick, Angela Jae Waanders, Lukas J.A. Stalpers, Mitchel S. Berger, Nalin Gupta, Charles David James, Claudia K. Petritsch, Daphne A. Haas-Kogan*

*Corresponding author for this work

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Purpose: 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, BRAFV600E and mTOR inhibitors in gliomas carrying specific genetic alterations of the MAPK pathway. Experimental Design:Weused human glioma lines containing BRAFV600E (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 BRAFV600E-expressing murine brain cells. Signaling inhibitors included everolimus (mTOR), PLX4720 (BRAFV600E), and AZD6244 (MEK1/2). Proliferation was determined using ATP-based assays. In vivo inhibitor activities were assessed in the BT40 PLGG xenograft model. Results: In BRAFV600E cells, the three possible doublet combinations of AZD6244, everolimus, and PLX4720 exhibited significantly greater effects on cell viability. In BRAFWT 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 BRAFV600E pediatric xenograft model BT40 showed the greatest survival advantage in mice treated with AZD6244 + PLX4720 (P < 0.01). Conclusions: In BRAFV600E tumors, combination of AZD6244 + PLX4720 is superior to monotherapy and to other combinatorial approaches. In BRAFWT pediatric gliomas, everolimus + AZD6244 is superior to either agent alone. KIAA1549:BRAFexpressing 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.

Original languageEnglish (US)
Pages (from-to)5312-5321
Number of pages10
JournalClinical Cancer Research
Volume22
Issue number21
DOIs
StatePublished - Nov 1 2016

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Olow, A., Mueller, S., Yang, X., Hashizume, R., Meyerowitz, J., Weiss, W., Resnick, A. C., Waanders, A. J., Stalpers, L. J. A., Berger, M. S., Gupta, N., James, C. D., Petritsch, C. K., & Haas-Kogan, D. A. (2016). BRAF status in personalizing treatment approaches for pediatric gliomas. Clinical Cancer Research, 22(21), 5312-5321. https://doi.org/10.1158/1078-0432.CCR-15-1101