Overcoming resistance to single-agent therapy for oncogenic BRAF gene fusions via combinatorial targeting of MAPK and PI3K/mTOR signaling pathways

Jain, PayalSilva, AmandaHan, Harry J.Lang, Shih-ShanZhu, YuankunBoucher, KatieSmith, Tiffany E.Vakil, AeshaDiviney, PatrickChoudhari, NamrataRaman, PichaiBusch, Christine M.Delaney, TimYang, XiaodongOlow, Aleksandra K.Mueller, SabineHaas-Kogan, DaphneFox, ElizabethStorm, Phillip B.Resnick, Adam C.Waanders, Angela J.2017-12-062017Jain, P., A. Silva, H. J. Han, S. Lang, Y. Zhu, K. Boucher, T. E. Smith, et al. 2017. “Overcoming resistance to single-agent therapy for oncogenic BRAF gene fusions via combinatorial targeting of MAPK and PI3K/mTOR signaling pathways.” Oncotarget 8 (49): 84697-84713. doi:10.18632/oncotarget.20949. http://dx.doi.org/10.18632/oncotarget.20949.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34493164Pediatric 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 via increased 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.en-USpediatric low-grade gliomaBRAF-fusionstrametinib and everolimusMAPK pathwayPI3K/mTOR pathwayOvercoming resistance to single-agent therapy for oncogenic BRAF gene fusions via combinatorial targeting of MAPK and PI3K/mTOR signaling pathwaysJournal Article2017-12-0610.18632/oncotarget.20949