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

## TL;DR

This study shows that combining PARP inhibitors with anti-angiogenic drugs can overcome resistance in IDH-mutant gliomas by targeting Prickle4-driven angiogenesis.

## Contribution

The study identifies Prickle4 as a novel mediator of resistance to PARP inhibition in IDH-mutant gliomas and proposes a combination therapy strategy.

## Key findings

- PARPi induces pro-inflammatory transcriptomic changes promoting tumor angiogenesis.
- Prickle4 is a critical mediator of PARPi-induced neovascularization and resistance.
- Combining PARPi with lenvatinib blocks Prickle4-driven angiogenesis and extends survival.

## 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.

IDH‐mutant gliomas exhibit sensitivity to PARP inhibitors (PARPi) owing to oncometabolite 2‐HG‐induced DNA repair defects. PARPi treatment induces resistance by upregulating Prickle4, which promotes VEGF‐driven angiogenesis. Combining PARPi veliparib with anti‐angiogenic lenvatinib blocks this pathway, causing tumor regression and prolonged survival in models, revealing a new adaptive resistance mechanism and supporting a promising combination strategy.