Acquired resistance to BRAF inhibition in BRAF^V600E mutant gliomas

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.