Related Experiment Video
Updated: May 8, 2026
Tumor Treating Field Therapy in Combination with Bevacizumab for the Treatment of Recurrent Glioblastoma
Published on: October 27, 2014
FGFR1 drives metabolic adaptation associated with temozolomide resistance in glioblastoma
Laura Zarzuela1, Ignacio G López-Cepero1, Kevin M Rattigan2
1Centro Andaluz de Biología Molecular y Medicina Regenerativa - CABIMER, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Universidad Pablo de Olavide, Fundación Progreso y Salud, Junta de Andalucía. Edif. CABIMER, Av. Américo Vespucio 24, Seville, 41092, Spain.
Abstract:
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.
Insights
Fibroblast Growth Factor Receptor 1 (FGFR1) drives resistance to temozolomide (TMZ) in glioblastoma by altering cell signaling and metabolism. Inhibiting FGFR1 restores TMZ sensitivity and improves outcomes in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Glioblastoma (GBM) presents significant therapeutic challenges due to high rates of therapy resistance.
- Temozolomide (TMZ) is a standard chemotherapy for GBM, but resistance frequently develops.
- Understanding resistance mechanisms is crucial for improving GBM patient outcomes.
Purpose of the Study:
- To investigate the molecular mechanisms underlying temozolomide (TMZ) resistance in glioblastoma (GBM).
- To identify key signaling pathways and metabolic alterations contributing to therapy resistance.
- To evaluate the therapeutic potential of targeting identified pathways in GBM.
Main Methods:
- Dissection of resistance mechanisms in GBM cells.
- Analysis of signaling and metabolic rewiring associated with TMZ resistance.
- Inhibition of Fibroblast Growth Factor Receptor 1 (FGFR1) pathway.
- Assessment of cell cycle arrest, DNA repair, and metabolic reprogramming (lipid catabolism, lipid peroxidation).
- Validation in preclinical animal GBM models.
Main Results:
- FGFR1 pathway identified as a major controller of signaling and metabolic rewiring in TMZ-resistant GBM.
- FGFR1 promotes p53-mediated cell cycle arrest and DNA repair in response to TMZ.
- FGFR1 regulates metabolic reprogramming, favoring lipid catabolism and preventing lipid peroxidation.
- FGFR1 inhibition reversed resistance, restoring TMZ sensitivity and inducing tumor cell death.
- Correlation found between FGFR1 expression and poor prognosis in GBM patients.
Conclusions:
- FGFR1 plays a critical role in mediating TMZ resistance in FGFR1-positive, p53 WT GBM.
- Targeting FGFR1 in combination with TMZ is a promising strategy to overcome therapy resistance.
- FGFR1 is a potential therapeutic target for improving treatment efficacy in GBM patients.
