%0 Thesis
%A Zarzuela Moncada, Laura
%T Interaction of FGFR1 and NOTCH2 signaling pathways in glioblastoma chemoresistance: molecular mechanisms, metabolic adaptations, and therapeutic implications
%D 2025
%U https://hdl.handle.net/10433/24557
%X Glioblastoma (GBM) remains one of the most aggressive brain cancers with poor prognosis and limited therapeutic options. Despite advances in understanding its molecular landscape, the current therapy offer only modest survival benefits due to the chemoresistance driven by tumor heterogeneity and molecular adaptations. This highlights the need for innovative strategies to overcome resistance and improve patient outcomes.The present study explores the role of FGFR1 in TMZ resistance, its interplay with Notch2 signaling, and its potential as a therapeutic target in GBM. Hence, we identified FGFR1 pathway as a central regulator of the signaling and metabolic rewiring linked with temozolomide (TMZ) resistance in GBM. FGFR1 inhibition was found to sensitize GBM cells to TMZ in an MGMT-methylated, p53 wild-type genetic context, a prevalent genetic profile in GBM. Transcriptomic and metabolomic analyses revealed FGFR1 disrupting the metabolic plasticity critical for TMZ resistance, while lipidomic profiling suggested ferroptosis as a mechanism underlying enhanced cell death induced by FGFR1 inhibition and TMZ co-treatment. Our results further indicated a correlation of FGFR1 and poor GBM prognosis. We also validated the dual treatment of FGFR1 inhibitor and TMZ in preclinical in vivo studies as a potential strategy to improve chemosensitivity in GBM. The study of the interplay between FGFR1 and Notch2 pathways showed the colocalization of both receptors at the cell membrane and a modulation of FGFR1 over Notch2 intracellular domain (N2ICD) levels. However, Notch2 signaling was not directly implicated in the resistance to TMZ in GBM. Interestingly, N2ICD localization within the mitochondria supports a role in mitochondria metabolism in GBM that requires further investigation.Collectively, this study identifies FGFR1 as a key regulator of TMZ resistance and a promising therapeutic target in GBM. This work establishes a foundation for innovative co-treatment strategies aimed at improving the therapeutic outcomes for GBM patients.
%K Mecanismos de acción de la quimioterapia
%K Biología molecular
%K Metabolismo humano
%K Marcadores tumorales
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