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.