LMNA-PRKDC axis enhances DNA repair and promotes chemoresistance in glioblastoma

TL;DR

This study identifies a new mechanism of chemotherapy resistance in glioblastoma involving the LMNA-PRKDC axis, which improves DNA repair and tumor survival.

Contribution

The discovery of the LMNA-PRKDC axis as a driver of temozolomide resistance in glioblastoma through enhanced DNA repair.

Findings

Resistant glioblastoma tumors show elevated LMNA and increased interaction with PRKDC, enhancing DNA repair.

Inhibiting PRKDC with KU57788 restores temozolomide sensitivity and reduces tumor growth in models.

High LMNA-PRKDC expression correlates with poor survival in glioblastoma patients.

Abstract

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.

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