Prickle4 Drives Microenvironmental Remodeling and Resistance to Parp Inhibition in IDH‐Mutant Glioma
Mutations in isocitrate dehydrogenase (IDH) genes sensitize gliomas to PARP inhibition (PARPi) by inducing epigenetic reprogramming of DNA damage repair circuits. However, tumors treated with PARPi eventually relapse despite initial responsiveness. In this study, it is demonstrated that the anti-angiogenic agent lenvatinib synergizes effectively with PARPi, resulting in substantial tumor regression and significantly extended survival. Genomic analysis of tumors reveals that PARPi induces widespread transcriptomic changes that are predominantly pro-inflammatory, thereby promoting tumor angiogenesis. Prickle4, a planar cell polarity protein, is identified as a critical mediator of PARPi-induced neovascularization. Targeting Prickle4 effectively overcomes PARPi resistance in these tumors. Collectively, these findings identified the Prickle4-mediated microenvironmental remodeling as the key resistance mechanism to PARPi, and support the therapeutic promise of multimodal therapy combining PARPi with anti-angiogenic agents for glioma treatment.
Authors
- Yulong Xiong (ORCID: https://orcid.org/0000-0001-5476-6405)
- Kevin Ling (ORCID: https://orcid.org/0000-0002-4872-5751)
- Jason T. Huse (ORCID: https://orcid.org/0000-0003-4514-0640)
- Yifan Yuan (ORCID: https://orcid.org/0000-0001-8645-3112)
- Zengxin Qi (ORCID: https://orcid.org/0000-0001-5206-9948)
- Chenyang Zhang (ORCID: https://orcid.org/0000-0002-9128-5376)
- Yuxiang Wang (ORCID: https://orcid.org/0000-0002-1261-3985)
- Ying Liu (ORCID: https://orcid.org/0000-0003-1662-9228)
- Zhao Zhang (ORCID: https://orcid.org/0000-0002-3757-8469)
- Bo Chen (ORCID: https://orcid.org/0000-0002-2216-2794)
- Xiuping Liu (ORCID: https://orcid.org/0000-0003-1935-950X)
- Yanyan Chen (ORCID: https://orcid.org/0000-0001-7882-7874)
- Ziwei Fu
- Shuyu Chen (ORCID: https://orcid.org/0009-0009-1762-0269)
- Hua Yang (ORCID: https://orcid.org/0000-0002-7248-9410)
- Timothy A. Chan
- Ju Yang
Institutions
- Cleveland Clinic (US)
- Shanghai Medical College of Fudan University (CN)
- The University of Texas MD Anderson Cancer Center (US)
- Chengdu Medical College (CN)
- Fudan University (CN)
- Pudong Medical Center (CN)
- Huashan Hospital (CN)
- Shanghai Center for Brain Science and Brain-Inspired Technology (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-11-14
- DOI
- https://doi.org/10.1002/advs.202503866
- Primary Topic
- Nuclear Structure and Function
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fred Hutchinson Cancer Research Center
- Memorial Sloan-Kettering Cancer Center
- National Natural Science Foundation of China
- Fudan University