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<p>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 <i>LMNA</i>–<i>PRKDC</i> 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 <i>LMNA</i> expression and increased physical interaction with <i>PRKDC</i>, 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 <i>LMNA</i>–<i>PRKDC</i>–associated DNA repair complex. Inhibition of <i>PRKDC</i> 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 <i>LMNA</i>–<i>PRKDC</i> co-expression as a hallmark of treatment-resistant, glioma stem-like cell populations. Importantly, high <i>LMNA</i>–<i>PRKDC</i> expression was associated with inferior survival outcomes in GBM patient cohorts. These results establish the <i>LMNA</i>–<i>PRKDC</i> axis as a functional driver of TMZ resistance through enhanced DNA repair capacity in stem-like tumor subpopulations. Our findings support pharmacologic inhibition of <i>PRKDC</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月21日

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  • Miranda R. Saathoff,
  • Rafal Chojak,
  • Rebecca X. Chen,
  • Hasaan A. Kazi,
  • Umme H. Faisal,
  • Jack M. Shireman,
  • Noah Drewes,
  • Cheol H. Park,
  • Xuesong Fan,
  • Sana A. Khan,
  • Irene Lazanyi,
  • Shivani Baisiwala,
  • C. David James,
  • Craig M. Horbinski,
  • Atique U. Ahmed

摘要

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.