PEAKS activation by PROTAC EPIC-0726 potentiates temozolomide in glioblastoma via K63/K48 ubiquitination-dependent ERK/AKT suppression and p21 stabilization
This study establishes PROTAC-mediated PTRF degradation as a mechanistically distinct manner to activate proteolysis strategy-enhanced temozolomide efficacy by ERK1/2/AKT kinase suppression and p21 stabilization (PEAKS) through the PTRF-RBX1 regulatory axis. The superior efficacy of EPIC-0726 over EPIC-1042, particularly in overcoming TMZ resistance, provides a paradigm-shifting therapeutic approach for GBM. Our findings warrant the clinical translation of EPIC-0726 as both a monotherapy and a backbone for combination regimens.
Authors
- Biao Hong
- Qixue Wang (ORCID: https://orcid.org/0000-0001-9350-9882)
- Xiaoteng Cui (ORCID: https://orcid.org/0000-0003-4994-147X)
- Sai Liang (ORCID: https://orcid.org/0000-0002-6306-5800)
- Dongyuan Su
- Eryan Yang
- Chunsheng Kang (ORCID: https://orcid.org/0000-0002-3255-3369)
- Yaqing Ding
- Yilin Zhao
- Shixue Yang
- Yuhao Liu (ORCID: https://orcid.org/0000-0002-1666-208X)
- Jixing Zhao
- Hanyi Xu
- Jiasheng Ju
- Longtao Cui
- Qi Zhan (ORCID: https://orcid.org/0000-0001-7925-4107)
- Chao Cheng (ORCID: https://orcid.org/0009-0002-9586-2131)
- Yanping Huang
Institutions
- Shandong University (CN)
- Chongqing University (CN)
- Tianjin Medical University General Hospital (CN)
- Ministry of Education (ME)
- Chongqing Cancer Hospital (CN)
- Qilu Hospital of Shandong University (CN)
Publication Details
- Journal
- Neuro-Oncology
- Published
- 2025-10-24
- DOI
- https://doi.org/10.1093/neuonc/noaf253
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.00