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

Ju Yang1, Hua Yang2, Yifan Yuan3

  • 1Department of Pathology, School of Basic Medical Sciences, Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200040, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|November 14, 2025
PubMed

Insights

Isocitrate dehydrogenase (IDH) mutations prime gliomas for PARP inhibition (PARPi). However, tumors develop resistance. Combining PARPi with lenvatinib, an anti-angiogenic agent, overcomes this resistance by targeting Prickle4, a key mediator of tumor angiogenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Mutations in isocitrate dehydrogenase (IDH) genes sensitize gliomas to PARP inhibition (PARPi).
  • Tumors treated with PARPi eventually relapse despite initial responsiveness, indicating resistance mechanisms.
  • Understanding these resistance mechanisms is crucial for developing effective glioma treatments.

Purpose of the Study:

  • To investigate the synergistic effects of lenvatinib and PARPi in IDH-mutant gliomas.
  • To identify the molecular mechanisms underlying tumor resistance to PARPi.
  • To explore therapeutic strategies to overcome PARPi resistance in gliomas.

Main Methods:

  • Genomic and transcriptomic analysis of gliomas.
  • In vivo studies evaluating tumor regression and survival.
  • Investigation of the role of Prickle4 in mediating PARPi resistance.

Main Results:

  • Lenvatinib synergizes with PARPi, leading to substantial tumor regression and extended survival.
  • PARPi induces pro-inflammatory transcriptomic changes, promoting tumor angiogenesis.
  • Prickle4 is identified as a critical mediator of PARPi-induced neovascularization and resistance.

Conclusions:

  • Prickle4-mediated microenvironmental remodeling is a key resistance mechanism to PARPi in gliomas.
  • Targeting Prickle4 effectively overcomes PARPi resistance.
  • Multimodal therapy combining PARPi with anti-angiogenic agents shows therapeutic promise for glioma treatment.
Keywords:
IDHPARPangiogenesisglioma

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