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 glioma.