use-cerebral-open-flow-microperfusion-for-longitudinal-collection

Use of Cerebral Open-Flow Microperfusion for the Longitudinal Collection of Interstitial Fluid in an Animal Model of Glioblastoma

Diseases of the central nervous system (CNS) manifest through a complex, dynamic network of intercellular communication. Glioblastoma (GBM), the most ...

Northwestern University

Glioblastoma (GBM) remains one of the deadliest primary brain tumors, with rapid recurrence and near-universal resistance to temozolomide (TMZ) limiting long-term survival. In this study, we identify a clinically actionable mechanism of resistance driven by the LMNA-PRKDC axis, which enhances DNA repair and tumor cell survival following TMZ treatment. Using patient-derived xenograft models of recurrent GBM, we demonstrate that resistant tumors exhibit elevated LMNA expression and increased physical interaction with PRKDC, a central regulator of non-homologous end joining (NHEJ). This interaction accelerates the repair of TMZ-induced DNA lesions, contributing to therapeutic failure. Proteomic profiling and targeted immunoprecipitation revealed a distinct LMNA-PRKDC-associated DNA repair complex. Inhibition of PRKDC with the ATP-competitive inhibitor KU57788 reversed resistance, restoring TMZ sensitivity and impairing tumor growth in vivo. Single-cell RNA sequencing of primary and recurrent GBM specimens further identified LMNA-PRKDC co-expression as a hallmark of treatment-resistant, glioma stem-like cell populations. Importantly, high LMNA-PRKDC expression was associated with inferior survival outcomes in GBM patient cohorts. These results establish the LMNA-PRKDC axis as a functional driver of TMZ resistance through enhanced DNA repair capacity in stem-like tumor subpopulations. Our findings support pharmacologic inhibition of PRKDC as a rational strategy to resensitize resistant GBM to standard chemotherapy and offer a foundation for future biomarker-driven clinical trials targeting DNA repair vulnerabilities in recurrent disease.

Umme H. Faisal

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