# 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.

## Key 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.