Acquired resistance to BRAF inhibition in BRAFV600E 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 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.
Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
Tsun-Wen
TW
Yao
Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
Jie
J
Zhang
Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.|Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
Michael
M
Prados
Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.|Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.|Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
William A
WA
Weiss
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.|Northwestern Medicine Developmental Therapeutics Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
C David
CD
James
Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.|Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
Theodore
T
Nicolaides
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000235:genetics*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism; D000094963:Axl Receptor Tyrosine Kinase
D000970:Antineoplastic Agents; D007211:Indoles; C528407:PLX 4720; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human
Axl; BRAFV600E; EGFR; PLX4720; glioma