In the present study, we employ complementary models and experimental strategies, including a Proximity-dependent Biotin Identification (BioID)-based proximal interactome profiling and CRISPR-engineered glioma cell lines, to investigate how secondary hits in the oncogene FGFR1 modulate cellular effects and oncogenic drive mediated by hotspot mutations. Here, FGFR1 is linked to central nervous system cancer.