journal article·2026-01Open access

Prickle4 Drives Microenvironmental Remodeling and Resistance to Parp Inhibition in IDH‐Mutant Glioma

Ju Yang, Hua Yang, Yifan Yuan, Chenyang Zhang, Ziwei Fu, Yanyan Chen, Yinghong Xiong, Shuyu Chen, Kexin Ling, Ying Liu, Jason T. Huse, Bo Chen, Timothy A. Chan, Zengxin Qi, Zhao Zhang, Xiuping Liu, Yuxiang Wang

Advanced Science· Volume 13· Issue 3

Abstract

Abstract 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.
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Research context

OpenAlex topics: Nuclear Structure and Function · Hippo pathway signaling and YAP/TAZ · Microtubule and mitosis dynamics

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Pathology School of Basic Medical Sciences Shanghai Fifth People's Hospital Fudan University Shanghai 200040 China

Department of Pathology School of Basic Medical Sciences Fudan University Shanghai 200040 China

Department of Neurosurgery National Center for Neurological Disorders Huashan Hospital Fudan University Shanghai 200040 China

Departments of Pathology and Translational Molecular Pathology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

Keymed Biosciences (Chengdu) Limited Chengdu Sichuan 610219 China

Center for Immunotherapy and Precision Immuno‐Oncology Cleveland Clinic Cleveland Ohio 44195 USA

Department of Neurosurgery Huashan Hospital Shanghai Medical College Fudan University Shanghai 200040 China

National Center for Neurological Disorders Shanghai 200040 China

Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration Shanghai 200040 China

MOE Key Laboratory of Metabolism and Molecular Medicine Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Fudan University Shanghai 200040 China

Department of Pathology School of Basic Medical Sciences Fudan University & Shanghai Pudong Hospital Fudan University Pudong Medical Center Shanghai 200032 China

Funding

National Natural Science Foundation of China · National Major Science and Technology Projects of China

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