Oncotarget

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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

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 _

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Oncotarget. 2017; 8:84697-84713. https://doi.org/10.18632/oncotarget.20949

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Abstract

Payal Jain1,2,3, Amanda Silva1, Harry J. Han2, Shih-Shan Lang1,2, Yuankun Zhu1,3, Katie Boucher1,2,3, Tiffany E. Smith1,2,3, Aesha Vakil4, Patrick Diviney5, Namrata Choudhari1,2,3, Pichai Raman3,6,7, Christine M. Busch 8, Tim Delaney1,2,3, Xiaodong Yang9, Aleksandra K. Olow10, Sabine Mueller9,11,12, Daphne Haas-Kogan13, Elizabeth Fox8, Phillip B. Storm1,2,3, Adam C. Resnick1,2,3,6,* and Angela J. Waanders3,8,14,*

1 Division of Neurosurgery, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

2 Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

3 Center for Data Driven Discovery in Biomedicine (D3b), The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

4 The Fred Hutchinson Cancer Research Center, Seattle, WA, USA

5 Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

6 Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

7 Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

8 Division of Oncology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

9 Division of Neurology, University of California, San Francisco, CA, USA

10 Amgen, South San Francisco, CA, USA

11 Department of Neurosurgery, University of California, San Francisco, CA, USA

12 Department of Pediatrics, University of California, San Francisco, CA, USA

13 Department of Radiation Oncology, Harvard Medical School, Boston, MA, USA

14 Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

* These authors are co-senior authors and have contributed equally to this work

Correspondence to:

Angela J. Waanders, email: waandersA@email.chop.edu

 

Keywords: pediatric low-grade glioma, BRAF-fusions, trametinib and everolimus, MAPK pathway, PI3K/mTOR pathway

Received: March 03, 2017 Accepted: August 23, 2017 Published: September 15, 2017

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.


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