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Combined BRAFV600E and MEK blockade for BRAFV600E-mutant gliomas

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Abstract

BRAFV600E is a common finding in glioma (about 10–60% depending on histopathologic subclassification). BRAFV600E monotherapy shows modest preclinical efficacy against BRAFV600E gliomas and also induces adverse secondary skin malignancies. Here, we examine the molecular mechanism of intrinsic resistance to BRAFV600E inhibition in glioma. Furthermore, we investigate BRAFV600E/MEK combination therapy that overcomes intrinsic resistance to BRAFV600E inhibitor and also prevents BRAFV600E inhibitor induced secondary malignancies. Immunoblotting and Human Phospho-Receptor Tyrosine Kinase Array assays were used to interrogate MAPK pathway activation. The cellular effect of BRAFV600E and MEK inhibition was determined by WST-1 viability assay and cell cycle analysis. Flanked and orthotopic GBM mouse models were used to investigate the in vivo efficacy of BRAFV600E/MEK combination therapy and the effect on secondary malignancies. BRAFV600E inhibition leads to recovery of ERK phosphorylation. Combined BRAFV600E and MEK inhibition prevents reactivation of the MAPK signaling, which correlates with decreased cell viability and augmented cell cycle arrest. Similarly, mice bearing BRAFV600E glioma showed reduced tumor growth when treated with a combination of BRAFV600E and MEK inhibitor compared to BRAFV600E inhibition alone. Additional benefit of BRAFV600E/MEK inhibition was reflected by reduced cutaneous squamous-cell carcinoma (cSCC) growth (a surrogate for RAS-driven secondary maligancies). In glioma, recovery of MAPK signaling upon BRAF inhibition accounts for intrinsic resistance to BRAFV600E inhibitor. Combined BRAFV600E and MEK inhibition prevents rebound of MAPK activation, resulting in enhanced antitumor efficacy and also reduces the risk of secondary malignancy development.

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Acknowledgements

This study was supported by grants from the St. Baldrick’s Foundation (TN), UCSF Resource Allocation program (TN), the Frank A Campini Foundation (TN), the National Institute for Neurological Disorders and Stroke (K08NS065268: TN; R01NS080619: CDJ), the National Cancer Institute (P50CA097257: TN, MP, CDJ; P30CA82103: WAW; U01CA176287: WAW; U54CA163155: WAW), the Pediatric Brain Tumor Foundation (WAW; TN) and the Samuel Waxman Cancer Research Foundation (WAW).

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Authors and Affiliations

  1. Department of Pediatrics, University of California San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA

    Jie Zhang, Tsun-Wen Yao, Sujatmi Hariono, Michael Prados, William A. Weiss & Theodore Nicolaides

  2. Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Tarry Building, 300 E Superior, Chicago, IL, 60611, USA

    Rintaro Hashizume & C. David James

  3. Department of Neurology, University of California San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA

    Krister J. Barkovich, Qi-Wen Fan & William A. Weiss

  4. Department of Neurological Surgery, University of California San Francisco, 1450 3rd Street, HD400, San Francisco, CA, 94158, USA

    Michael Prados, William A. Weiss & Theodore Nicolaides

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  1. Jie Zhang
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  2. Tsun-Wen Yao
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  3. Rintaro Hashizume
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Correspondence to Theodore Nicolaides.

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Zhang, J., Yao, TW., Hashizume, R. et al. Combined BRAFV600E and MEK blockade for BRAFV600E-mutant gliomas. J Neurooncol 131, 495–505 (2017). https://doi.org/10.1007/s11060-016-2333-4

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  • DOI: https://doi.org/10.1007/s11060-016-2333-4

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