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

Area of Science:

• Neuro-oncology
• Cancer Biology
• Molecular Therapeutics

Background:

• Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis.
• Resistance to temozolomide (TMZ) chemotherapy is a major challenge in GBM treatment, leading to rapid recurrence.
• Identifying mechanisms of TMZ resistance is critical for developing effective therapies.

Purpose of the Study:

• To elucidate a novel mechanism of TMZ resistance in glioblastoma.
• To investigate the role of the LMNA-PRKDC axis in DNA repair and therapeutic resistance.
• To evaluate PRKDC inhibition as a strategy to overcome TMZ resistance in GBM.

Main Methods:

• Utilized patient-derived xenograft models of recurrent GBM.
• Employed proteomic profiling and targeted immunoprecipitation to identify protein interactions.
• Performed single-cell RNA sequencing on primary and recurrent GBM specimens.
• Assessed the efficacy of PRKDC inhibition using KU57788 in vivo.

Main Results:

• Elevated LMNA expression and increased physical interaction with PRKDC were observed in resistant GBM tumors.
• The LMNA-PRKDC complex enhances repair of TMZ-induced DNA damage, contributing to therapeutic failure.
• PRKDC inhibition with KU57788 restored TMZ sensitivity and reduced tumor growth.
• LMNA-PRKDC co-expression identified treatment-resistant, glioma stem-like cell populations and correlated with poor survival.

Conclusions:

• The LMNA-PRKDC axis drives TMZ resistance in GBM via enhanced DNA repair in stem-like cells.
• Pharmacologic inhibition of PRKDC is a promising strategy to resensitize resistant GBM to chemotherapy.
• These findings provide a basis for biomarker-driven clinical trials targeting DNA repair vulnerabilities in recurrent GBM.