Acquired resistance to BRAF inhibition in BRAFV600E mutant gliomas

Abstract

// Tsun-Wen Yao 1 , Jie Zhang 1 , Michael Prados 1, 2 , William A. Weiss 1, 2, 3 , C. David James 4, 5 , Theodore Nicolaides 1, 2 1 Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA 2 Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA 3 Department of Neurology, University of California San Francisco, San Francisco, CA, USA 4 Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA 5 Northwestern Medicine Developmental Therapeutics Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Correspondence to: Tsun-Wen Yao, email: Tsunwen.Yao@ucsf.edu Theodore Nicolaides, email: Theodore.Nicolaides@ucsf.edu Keywords: BRAF V600E , 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 BRAF V600E mutation. Small molecule inhibitors that selectively target BRAF V600E are FDA approved for melanoma and have shown significant efficacy in treating BRAF V600E glioma in pre-clinical trials. Despite showing initial anti-tumor activity, acquired drug resistance significantly limits the benefit from being treated with BRAF V600E inhibitors. Here, we have identified molecular responses to BRAF V600E inhibitor treatment in human glioma models that have substantial clinical implications. Specifically, we show that BRAF V600E inhibitor resistant cells upregulate pro-survival mediators such as Wnt, and additionally increase receptor tyrosine kinase activity, including EGFR and Axl, promoting resistance to BRAF V600E inhibition. Our results suggest strategies to circumvent acquired resistance to BRAF V600E inhibitor therapy, and thereby improve outcomes for patients with BRAF V600E gliomas.