Oncotarget

Research Papers:

Acquired resistance to BRAF inhibition in BRAFV600E mutant gliomas

Tsun-Wen Yao _, Jie Zhang, Michael Prados, William A. Weiss, C. David James and Theodore Nicolaides

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Oncotarget. 2017; 8:583-595. https://doi.org/10.18632/oncotarget.11882

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Abstract

Tsun-Wen Yao1, Jie Zhang1, Michael Prados1,2, William A. Weiss1,2,3, C. David James4,5, Theodore Nicolaides1,2

1Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA

2Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA

3Department of Neurology, University of California San Francisco, San Francisco, CA, USA

4Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

5Northwestern Medicine Developmental Therapeutics Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

Correspondence to:

Tsun-Wen Yao, email: [email protected]

Theodore Nicolaides, email: [email protected]

Keywords: BRAFV600E, glioma, PLX4720, EGFR, Axl

Received: October 09, 2015     Accepted: August 27, 2016     Published: September 07, 2016

ABSTRACT

Activating mutation of BRAF is a common finding in pediatric gliomas. As many as 14% of high grade and up to 66% of certain subtypes of low grade pediatric glioma have the BRAFV600E mutation. Small molecule inhibitors that selectively target BRAFV600E are FDA approved for melanoma and have shown significant efficacy in treating BRAFV600E glioma in pre-clinical trials. Despite showing initial anti-tumor activity, acquired drug resistance significantly limits the benefit from being treated with BRAFV600E inhibitors. Here, we have identified molecular responses to BRAFV600E inhibitor treatment in human glioma models that have substantial clinical implications. Specifically, we show that BRAFV600E inhibitor resistant cells upregulate pro-survival mediators such as Wnt, and additionally increase receptor tyrosine kinase activity, including EGFR and Axl, promoting resistance to BRAFV600E inhibition. Our results suggest strategies to circumvent acquired resistance to BRAFV600E inhibitor therapy, and thereby improve outcomes for patients with BRAFV600E gliomas.


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