A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas Journal Article
| Authors: | Sun, Y.; Alberta, J. A.; Pilarz, C.; Calligaris, D.; Chadwick, E. J.; Ramkissoon, S. H.; Ramkissoon, L. A.; Garcia, V. M.; Mazzola, E.; Goumnerova, L.; Kane, M.; Yao, Z.; Kieran, M. W.; Ligon, K. L.; Hahn, W. C.; Garraway, L. A.; Rosen, N.; Gray, N. S.; Agar, N. Y.; Buhrlage, S. J.; Segal, R. A.; Stiles, C. D. |
| Article Title: | A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas |
| Abstract: | Background. Activating mutations or structural rearrangements in BRAF are identifed in roughly 75% of all pediatric low-grade astrocytomas (PLGAs). However, frst-generation RAF inhibitors approved for adult melanoma have poor blood-brain penetrance and are only effective on tumors that express the canonical BRAFV600E oncoprotein, which functions as a monomer. These drugs (type I antagonists that target the "DFG-in" conformation of the kinase) fail to block signaling via KIAA1549:BRAF, a truncation/fusion BRAF oncoprotein which functions as a dimer and is found in the most common form of PLGA. Methods. A panel of small molecule RAF inhibitors (including type II inhibitors, targeting the "DFG-out" conformation of the kinase) was screened for drugs showing effcacy on murine models of PLGA and on authentic human PLGA cells expressing KIAA1549:BRAF. Results. We identify a type II RAF inhibitor that serves as an equipotent antagonist of BRAFV600E, KIAA1549:BRAF, and other noncanonical BRAF oncoproteins that function as dimers. This drug (MLN2480, also known as TAK-580) has good brain penetrance and is active on authentic human PLGA cells in brain organotypic cultures. Conclusion. MLN2480 may be an effective therapeutic for BRAF mutant pediatric astrocytomas. © 2017 The Author(s). |
| Keywords: | mln2480; pediatric low-grade astrocytoma; raf dimers |
| Journal Title: | Neuro-Oncology |
| Volume: | 19 |
| Issue: | 6 |
| ISSN: | 1522-8517 |
| Publisher: | Oxford University Press |
| Date Published: | 2017-06-01 |
| Start Page: | 774 |
| End Page: | 785 |
| Language: | English |
| DOI: | 10.1093/neuonc/now261 |
| PROVIDER: | scopus |
| PMCID: | PMC5464455 |
| PUBMED: | 28082416 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 July 2017 -- Source: Scopus |
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