EGFR blockade prevents glioma escape from BRAFV600E targeted therapy
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Tsun-Wen Yao1,*, Jie Zhang1,*, Michael Prados1,2, William A. Weiss1,2,3, C. David James4,5, Theodore Nicolaides1,2
1Departments of Pediatrics, University of California San Francisco, San Francisco, CA, USA
2Departments of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA
3Departments of Neurology, University of California San Francisco, San Francisco, CA, USA
4Departments of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
5Northwestern Medicine Developmental Therapeutics Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
*These authors have contributed equally to this work
Tsun-Wen Yao, e-mail: Tsunwen.Yao@ucsf.edu
Theodore Nicolaides, e-mail: Theodore.Nicolaides@ucsf.edu
Keywords: BRAFV600E, EGFR, glioma, PLX4720, PTPN9
Received: February 17, 2015 Accepted: May 08, 2015 Published: May 22, 2015
Mutational activation of BRAF (BRAFV600E) occurs in pediatric glioma and drives aberrant MAPK signaling independently of upstream cues. Targeted monotherapy against BRAFV600E displays efficacy in pre-clinical models of glioma, however xenograft tumors adapt rapidly and escape from the growth-inhibitory effects of BRAF-targeted therapy. Here, we show that intrinsic resistance to a BRAFV600E specific inhibitor stems, in part, from feedback activation of EGFR and downstream signaling pathways. BRAFV600E inhibition suppresses MAPK signaling, which in turn downregulates the EGFR phosphatase PTPN9, resulting in sustained EGFR phosphorylation and enhanced EGFR activity. We demonstrated that overexpression of PTPN9 reduces EGFR phosphorylation and cooperates with BRAFV600E inhibitor PLX4720 to reduce MAPK and Akt signaling, resulting in decreased glioma cell viability. Moreover, pharmacologic inhibition of EGFR combined with inhibition of BRAFV600E to reduce growth of glioma cell lines and orthotopic glioma xenograft by decreasing tumor cell proliferation while increasing apoptosis, with resultant significant extension of animal subject survival. Our data support clinical evaluation of BRAFV600E and EGFR targeted therapy in treating BRAFV600E glioma.
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