Combined inhibition of SHP2 overcomes adaptive resistance to type 1 BRAF inhibitors in BRAF V600E-driven high-grade glioma.

ABSTRACT:

Background

BRAF-mutant gliomas can be targeted therapeutically using BRAF-selective inhibitors, yet responses are often transient due to adaptive resistance through reactivation of RAS-ERK signaling. Here, we evaluate the role of SHP2, a central regulator of RAS activity, and SHP2 inhibitors in overcoming resistance to BRAF inhibitors in glioma.

Methods

RNAseq and protein expression in human tissue samples and glioma cell lines were used to identify resistance mechanisms. BRAF p.V600E glioma cell lines were tested to evaluate the impact of combined SHP2 and BRAF inhibition on ERK pathway activity, cell growth/death, and tumor forming ability. In vivo studies utilized heterotopic and orthotopic cell lines and patient-derived xenografts (PDX).

Results

We observed

SUBMITTER: Ayanlaja AA 

PROVIDER: S-EPMC12400027 | biostudies-literature | 2025 Jan-Dec

REPOSITORIES: biostudies-literature