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Methylation array of cultured GBM models to create surrogate CNV profiles

ABSTRACT: Background: Epidermal growth factor receptor (EGFR) amplification occurs in ~50% of IDH-wildtype glioblastoma (GBM) cases, frequently accompanied by expression of the oncogenic EGFRvIII variant. Although EGFR represents an attractive therapeutic target, EGFR-directed therapies have shown limited clinical efficacy in GBM. Resistance to kinase inhibitors is frequently attributed to activation of compensatory signaling pathways (“kinome rewiring”). We therefore investigated whether EGFR inhibition in GBM induces broad adaptive kinase responses that could be co-targeted to overcome resistance. Methods: We molecularly profiled 29 patient-derived GBM cell lines for EGFR status and selected five representative models spanning distinct EGFR amplification states for functional analyses. Cells were treated with EGFR inhibitors and responses were assessed using 72-hour viability assays, time-resolved immunoblotting, and phosphoproteomics (LC-MS/MS) with kinase activity inference. Results: EGFR inhibitors preferentially impaired viability in EGFR-driven models and transiently reduced EGFR phosphorylation during the initial response. However, partial restoration of EGFR phosphorylation and downstream signaling occurred after 24 hours of continuous inhibitor exposure. Phosphoproteomics revealed no evidence of broad kinome rewiring within this timeframe but instead identified increased EGFR protein levels associated with restored EGFR pathway activity. The phosphorylated-to-total EGFR ratio remained relatively stable, consistent with sustained target engagement despite signaling rebound. Conclusions: Early adaptive responses to EGFR inhibition in GBM were not characterized by broad kinome rewiring but by restoration of EGFR signaling associated with increased EGFR abundance. These findings suggest that adaptive signaling remains largely EGFR-dependent despite continued inhibitor exposure, identifying regulation of EGFR abundance as a potential contributor to therapeutic resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE342610 | GEO | 2026/08/07

REPOSITORIES: GEO

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Project description:In this study the investigators looked at adaptive reprogramming impact on the kinome when a MEK inhibitor called GSK1120212 (trametinib) was administered in a "window of opportunity" trial. GSK1120212 is not yet approved by the FDA for use in breast cancer patients. The investigators gave GSK1120212 for a short period of time (one week) to examine MEK and the other kinase expression in cancer cells both before and after the study drug is given. The investigators gave this drug for research purposes only. The length of time it was given is not intended to treat cancer. Recently researchers at UNC developed a process that can comprehensively profile the majority of the individual kinases in the kinome and examine the impact on kinase expression of kinase inhibitors (Duncan et al, Cell 2012, PMID: 22500798). This can tell us which kinases need to be concurrently blocked to augment responsiveness and prevent acquired resistance so that the investigators can design the best combinations of kinase blocking drugs for triple negative breast cancer. This is especially important for individuals with triple negative breast cancer (TNBC) because there are no targeted drugs available that can block molecules that affect tumor growth. The investigators believe that kinase-blocking drugs have the potential to be a more effective treatment for people with TNBC. In this recently published study (Zawistowski et al, Cancer Discovery 2017, PMID: 28108460), TNBC patients treated with trametinib for 7 days resulted in a transcriptional response characterized by significant reprogramming of the tyrosine kinome, and this adaptive bypass response in human tumors was found to be similar to that seen in preclinical models including TNBC cell lines and mouse xenografts. In this study we also examined whether reprogramming differed between TNBC molecular subtypes, finding that basal-like and claudin-low human TNBC cells and mouse tumor subtypes had different adaptive transcriptional responses to MEK-ERK inhibition. Mechanistically we found that genome-wide enhancer remodeling drove the adaptive transcriptional response, suggesting that epigenetic approaches to reprogramming may be more durable than kinase inhibitor polypharmacology.

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Methylation array of cultured GBM models to create surrogate CNV profiles

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