Acquired resistance to BRAF inhibition in BRAFV600E mutant gliomas

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)583-595
Number of pages13
JournalOncotarget
Volume8
Issue number1
DOIs
StatePublished - 2017

Keywords

  • Axl
  • BRAF
  • EGFR
  • Glioma
  • PLX4720

ASJC Scopus subject areas

  • Oncology

Fingerprint

Dive into the research topics of 'Acquired resistance to BRAF inhibition in BRAF<sup>V600E</sup> mutant gliomas'. Together they form a unique fingerprint.

Cite this