Ceballos-Chavez, M. | Search bioRxiv

bioRxiv2025

FGFR1 inhibition prevents metabolic adaptation associated with therapy resistance in glioblastoma

Recurrent therapy resistance is a major limitation in clinical efficacy and for the outcome of glioblastoma (GBM) patients, positioning GBM among the tumor types with the poorest survival outcomes. In this work, we dissected resistance mechanisms in GBM, which resulted in the identification of FGFR1 pathway as a major regulator of the signaling and metabolic rewiring associated with temozolomide (TMZ) resistance in GBM. Hence, we described a mechanism of resistance that operates at two major levels. First, a p53-mediated regulation of cell cycle inducing cell cycle arrest to allow DNA repair in response to TMZ. And second, a complete metabolic rewiring promoting lipid catabolism and preventing lipid peroxidation. Both the p53-mediated response and the metabolic adaptation are controlled by FGFR1, as inhibition of the FGFR1 pathway completely abolishes this signaling and metabolic reprograming, restoring sensitivity to TMZ. Our results also indicated a correlation of FGFR1 levels with poor prognosis in GBM patients, and validated the treatment of TMZ in combination with FGFR1 inhibitors as an efficient strategy to induce tumor cell death in pre-clinical animal models. This data position the receptor FGFR1 as a very promising candidate for evaluation in future clinical approaches to limit the development of therapy resistance to TMZ in GBM patients.

cancer biology↗

bioRxiv2022

Serum-dependent recruitment of the chromatin remodeler CHD8 to promoters is mediated by the ERK-ELK pathway

Chromodomain helicase DNA binding protein 8 (CHD8) is a chromatin remodeler of the SNF2 family involved in gene transcription regulation. It has been shown that CHD8 is required for cell proliferation, cell differentiation and central nervous system development. In fact, CHD8 haploinsufficiency causes a human syndrome characterized by autism, macrocephaly, gastrointestinal complaints and some other clinical characteristics. However, the mechanism by which CHD8 controls transcription and how it is recruited to its targets in the chromatin is still unclear. We have previously shown that serum depletion causes that CHD8 detaches from chromatin. Here we demonstrate that serum-dependent recruitment of CHD8 to promoters requires the extracellular signal-regulated kinase (ERK)/ ETS-like (ELK) branch of the mitogen-activated protein kinase (MAPK) pathway. Our analysis of genomic occupancy data shows that CHD8 binding sites were strongly enriched in ELK1 and ELK4 DNA binding motifs and that CHD8 and ELK1 co-occupy multiple transcription start sites. We show that ELK1 and ELK4 are required for normal recruitment of CHD8 to the promoters of CCNA2, CDC6, CCNE2, BRCA2 and MYC genes. However, CHD8 is dispensable for ELK1 and ELK4 binding. Genome wide transcriptomic analysis evidenced that serum-dependent activation of a subset of immediate early genes, including the well-known ELK1 target gene FOS, was impaired upon depletion of CHD8. In summary, our results uncover the role of the ERK/ELK pathway in CHD8 recruitment to chromatin and provide evidences indicating a role of CHD8 in regulating serum-dependent transcription.

molecular biology↗