Response and resistance to BRAFV600E inhibition in gliomas: Roadblocks ahead?

Abstract

BRAFV600E represents the most common BRAF mutation in all human cancers. Among central nervous system (CNS) tumors, BRAFV600E is mostly found in pediatric low-grade gliomas (pLGG, ~20%) and, less frequently, in pediatric high-grade gliomas (pHGG, 5-15%) and adult glioblastomas (GBM, ~5%). The integration of BRAF inhibitors (BRAFi) in the treatment of patients with gliomas brought a paradigm shift to clinical care. However, not all patients benefit from treatment due to intrinsic or acquired resistance to BRAF inhibition. Defining predictors of response, as well as developing strategies to prevent resistance to BRAFi and overcome post-BRAFi tumor progression/rebound growth are some of the main challenges at present in the field. In this review, we outline current achievements and limitations of BRAF inhibition in gliomas, with a special focus on potential mechanisms of resistance. We discuss future directions of targeted therapy for BRAFV600E mutated gliomas, highlighting how insights into resistance to BRAFi could be leveraged to improve outcomes.

BRAF V600E in a preclinical model of pleomorphic Xanthoastrocytoma: Analysis of the tumor microenvironment and immune cell infiltration dynamics in vivo

“…Clinical evaluation of BRAF inhibitors for treating BRAF-mutated pLGG showed toxicity and acquired resistance to these treatments. 4 , 7 , 15 , 23 Moreover, there is a paucity of immunocompetent BRAF-mutated glioma murine models for the scientific community to elucidate these mechanisms of resistance. 24 Here, we present a novel immunocompetent RCAS-BRAF V600E murine model that resembles diffuse glioma PXA pLGG-like tumors.…”

“…Although overall survival in pLGG is considered relatively favorable compared with other brain tumors, several factors, including tumor location, partial surgical resection, limitation of radiation therapy in young patients, chemoresistance to conventional therapies, resistance to BRAF inhibitors in BRAF-mutated patients, and occurrence of neurofibromatosis type 1 (NF1) mutations, significantly affect long-term survival rates. 2 , 3 , 4 , 5 , 6 , 7 …”

Ezrin Inhibition Overcomes Acquired Resistance to Vemurafenib in BRAFV600E-Mutated Colon Cancer and Melanoma Cells In Vitro

“…The BRAFV600E mutation has been shown to affect the tumour immune microenvironment in colorectal cancer [ 31 ], melanoma [ 32 ] and glioblastoma [ 33 ], and intrinsic resistance to BRAFV600E inhibition may stem from the changes in the tumour microenvironment resulting in the activation of the compensatory signals and/or reactivation of the targeted pathway [ 33 ].…”

Clinicopathological analysis of BRAF and non-BRAF MAPK pathway-altered gliomas in paediatric and adult patients: a single-institution study of 40 patients

“…54 Additionally, intrinsic resistance to targeted therapy may be caused by preexisting concomitant genetic alterations and physical factors related to blood-brain barrier and tumour microenvironment. 55 Another subset of GBMs is enriched with potentially targetable RTK fusions involving EGFR, NTRK, FGFR and MET with a variety of partners, 23 56-58 yet the effectiveness of tyrosine kinase inhibitors is similarly questionable. 59 In this study a There are several limitations in this study.…”