Overcoming Resistance to Single-agent Therapy for Oncogenic BRAF Gene Fusions via Combinatorial Targeting of MAPK and PI3K/mTOR Signaling Pathways


September 15, 2017
Payal Jain, Amanda Silva, Harry J. Han, Shih-Shan Lang, Yuankun Zhu, Katie Boucher, Tiffany E. Smith, Aesha Vakil, Patrick Diviney, Namrata Choudhari, Pichai Raman, Christine M. Busch, Tim Delaney, Xiaodong Yang, Aleksandra K. Olow, Sabine Mueller, Daphne Haas-Kogan, Elizabeth Fox, Phillip B. Storm, Adam C. Resnick and Angela J. Waanders


Pediatric low-grade gliomas (PLGGs) are frequently associated with activating BRAF gene fusions, such as KIAA1549-BRAF, that aberrantly drive the mitogen activated protein kinase (MAPK) pathway. Although RAF inhibitors (RAFi) have been proven effective in BRAF-V600E mutant tumors, we have previously shown how the KIAA1549-BRAF fusion can be paradoxically activated by RAFi. While newer classes of RAFi, such as PLX8394, have now been shown to inhibit MAPK activation by KIAA1549-BRAF, we sought to identify alternative MAPK pathway targeting strategies using clinically relevant MEK inhibitors (MEKi), along with potential escape mechanisms of acquired resistance to single-agent MAPK pathway therapies. We demonstrate effectiveness of multiple MEKi against diverse BRAF-fusions with novel N-terminal partners, with trametinib being the most potent. However, resistance to MEKi or PLX8394 develops viaincreased RTK expression causing activation of PI3K/mTOR pathway in BRAF-fusion expressing resistant clones. To circumvent acquired resistance, we show potency of combinatorial targeting with trametinib and everolimus, an mTOR inhibitor (mTORi) against multiple BRAF-fusions. While single-agent mTORi and MEKi PLGG clinical trials are underway, our study provides preclinical rationales for using MEKi and mTORi combinatorial therapy to stave off or prevent emergent drug-resistance in BRAF-fusion driven PLGGs.