2. Academic Validation
  3. Combined inhibition of WEE1 by AZD1775 synergistically enhances CX-5461 mediated DNA damage and induces cytotoxicity in glioblastoma

Combined inhibition of WEE1 by AZD1775 synergistically enhances CX-5461 mediated DNA damage and induces cytotoxicity in glioblastoma

  • Tissue Cell. 2025 Aug 18:97:103093. doi: 10.1016/j.tice.2025.103093.
Meng Cheng 1,  Rui Wang 1,  Ying Pang 1,  Xu Chen 1,  Jing Zhang 2,  Chunlong Zhong 3
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China.
  • 2 Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China; State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China; Institute for Advanced Study, Tongji University, Shanghai, 20092, China. Electronic address: zhangjingwt@tongji.edu.cn.
  • 3 Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China. Electronic address: drchunlongzhong@tongji.edu.cn.
PMID: 40839955 DOI: 10.1016/j.tice.2025.103093
Abstract

Glioblastoma (GBM) is an extremely aggressive type of central nervous system tumors that poses treatment challenges due to its resistance to DNA-damaging therapies. G-quadruplexes (G4) are non-canonical DNA structures involved in genomic stability and transcription regulation, and they have emerged as potential therapeutic targets. Originally developed as an RNA polymerase I inhibitor, CX-5461 has been demonstrated to enhance G4 stabilization and induce DNA damage; however, its effects on GBM remain underexplored. This study investigated the effects of CX-5461 on GBM cell biological functions. CX-5461 treatment significantly inhibited DNA replication and induced Apoptosis in GBM. S-phase arrest in cell cycle analysis indicated replication stress, and DNA damage assays revealed extensive double-strandbreaks. CX-5461 disrupted the DNA damage response by stabilizing G4 structures, resulting in sustained DNA damage accumulation. Moreover, the combined administration of CX-5461 and the Wee1 Inhibitor AZD1775 synergistically decreased cell proliferation and enhanced cell Apoptosis. Consequently, these results suggest that CX-5461 inhibited GBM progression by stabilizing G4, causing replication stress and exacerbating DNA damage. Targeting G4 structures, especially when combined with checkpoint inhibitors, provides a hopeful therapeutic approach to improve the effectiveness of GBM therapy.

Keywords

Cell cycle; DNA damage; DNA replication; G-quadruplex; Glioblastoma.

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