FGFR1 drives metabolic adaptation associated with temozolomide resistance in glioblastoma.

Therapy resistance is a major limitation in therapeutic efficacy for glioblastoma (GBM) patients, positioning GBM among the deadliest tumor types. In this work, we have dissected resistance mechanisms in GBM, which resulted in the identification of FGFR1 pathway as a major controller of the signaling and metabolic rewiring associated to temozolomide (TMZ) resistance. Hence, in FGFR1-positive, p53 WT GBM cells, FGFR1 controls a p53-mediated cell cycle arrest to allow DNA repair in response to TMZ. FGFR1 also regulates a complete metabolic rewiring promoting lipid catabolism and preventing lipid peroxidation. Indeed, FGFR1 inhibition completely abolishes this signaling and metabolic reprograming, restoring sensitivity to TMZ. Our results also indicated a correlation of FGFR1 with poor prognosis in GBM patients, and validated the dual treatment with TMZ and FGFR1 inhibitors as an efficient strategy to induce tumor cell death in FGFR1-positive, p53 WT pre-clinical animal GBM models. These data position FGFR1 as a promising candidate for future clinical evaluation to limit therapy resistance to TMZ in FGFR1-positive GBM patients.