EGFR blockade prevents glioma escape from BRAFV600E targeted therapy

// Tsun-Wen Yao 1, * , Jie Zhang 1, * , Michael Prados 1, 2 , William A. Weiss 1, 2, 3 , C. David James 4, 5 , Theodore Nicolaides 1, 2 1 Departments of Pediatrics, University of California San Francisco, San Francisco, CA, USA 2 Departments of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA 3 Departments of Neurology, University of California San Francisco, San Francisco, CA, USA 4 Departments of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA 5 Northwestern Medicine Developmental Therapeutics Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA * These authors have contributed equally to this work Correspondence to: Tsun-Wen Yao, e-mail: Tsunwen.Yao@ucsf.edu Theodore Nicolaides, e-mail: Theodore.Nicolaides@ucsf.edu Keywords: BRAF V600E , EGFR, glioma, PLX4720, PTPN9 Received: February 17, 2015 Accepted: May 08, 2015 Published: May 22, 2015 ABSTRACT Mutational activation of BRAF (BRAF V600E ) occurs in pediatric glioma and drives aberrant MAPK signaling independently of upstream cues. Targeted monotherapy against BRAF V600E 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 BRAF V600E specific inhibitor stems, in part, from feedback activation of EGFR and downstream signaling pathways. BRAF V600E 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 BRAF V600E inhibitor PLX4720 to reduce MAPK and Akt signaling, resulting in decreased glioma cell viability. Moreover, pharmacologic inhibition of EGFR combined with inhibition of BRAF V600E 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 BRAF V600E and EGFR targeted therapy in treating BRAF V600E glioma.