Lg-25pediatric Low-grade Gliomas With Craf Gene Fusions Respond Differentially to Targeted Therapeutics Based on Dimerization Profiles
Year: 2016
Type: article
Abstract: Pediatric low-grade gliomas (PLGGs) are the most common brain tumors in children. PLGGs have been defined by activating BRAF gene mutations/fusions that dysregulate the mitogen-associated protein kinase (MAPK) pathway, leading to clinical testing of MAPK inhibitors for PLGGs. However, recent large-scale sequencing studies have identified novel CRAF (or RAF1) fusions, QKI-RAF1 and SRGAP3-RAF1, as potential PLGG driver mutations. As CRAF and BRAF are shared targets of MAPK therapeutics, we sought to investigate the mechanistic and response of CRAF fusions to clinically relevant RAF inhibitors and downstream pathway inhibitors. We focused on comparing the effects and dependency on RAF dimerization for successful targeting. Using heterologous model systems, we found that CRAF fusions do not respond to RAF inhibitors, show partial response to single-agent MEK inhibitors, but robustly respond to combinatorial targeting of both MAPK and PI3K pathways and novel RAF dimer inhibitors. Upon comparing the homo- and hetero-dimerization profiles of QKI-RAF1and BRAF fusions in the presence of RAF inhibitors, we found that QKI-RAF1 retains robust homo- and hetero-dimerization that, in contrast, are disrupted in BRAF fusions that respond to RAF inhibitors. This suggests that dimerization is essential for MAPK pathway activation and determines responsiveness to RAF inhibitors. Furthermore, we found that the novel RAF dimer inhibitor, LY3009120, stabilized CRAF fusions in an inactive dimer conformation and suppressed oncogenic potential. Overall, CRAF fusions are distinct from BRAF fusions in responsiveness to targeted therapies. Our study suggests that molecular classification of PLGGs should inform therapeutic intervention of RAF-altered PLGGs even within RAF-mutant subtypes.
Source: Neuro-Oncology
Authors: Payal Jain, Tamara Fierst, Amanda Silva, Aesha Vakil, Harry Han, Phillip J. Storm, Angela J. Waanders, Adam Resnick
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2433193016