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

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

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Title: Overcoming resistance to single-agent therapy for oncogenic BRAF gene fusions via combinatorial targeting of MAPK and PI3K/mTOR signaling pathways
Author: Jain, Payal; Silva, Amanda; Han, Harry J.; Lang, Shih-Shan; Zhu, Yuankun; Boucher, Katie; Smith, Tiffany E.; Vakil, Aesha; Diviney, Patrick; Choudhari, Namrata; Raman, Pichai; Busch, Christine M.; Delaney, Tim; Yang, Xiaodong; Olow, Aleksandra K.; Mueller, Sabine; Haas-Kogan, Daphne; Fox, Elizabeth; Storm, Phillip B.; Resnick, Adam C.; Waanders, Angela J.

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Citation: Jain, 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.
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Abstract: 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 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.
Published Version: doi:10.18632/oncotarget.20949
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689567/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:34493164
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