Abstract High-grade glioma (HGG), including glioblastoma (GBM), remains one of the most aggressive and therapeutically resistant brain malignancies, with limited effective treatment options. While numerous clinical trials have explored molecularly targeted therapies, the intrinsic heterogeneity and lack of consistent predictive biomarkers have limited the success of biomarker-based precision approaches. In this study, we evaluated the efficacy of a drug combination targeting protein degradation and nuclear export (PDNE) pathways across a panel of patient-derived glioma (PDG) models. Although this therapeutic strategy has shown promise in other cancers, its potential in HGG has not been previously explored. Our results demonstrated that PDNE treatment exerted consistent and potent anti-tumor effects across multiple PDG lines, including a unique matched primary-recurrent pair, highlighting its broad activity across GBM subtypes. Transcriptomic profiling of treated PDGs revealed marked alterations in gene expression, including suppression of pro-survival signaling and restoration of tumor suppressor proteins such as p53 and p21, indicating a reactivation of tumor-suppressive mechanisms. Notably, we identified differentially expressed genes enriched in the G2–M checkpoint and mitotic spindle pathways following treatment, suggesting that PDNE may induce cell cycle arrest in a p53-dependent manner. Together, these findings provide mechanistic insight into how PDNE combination therapy disrupts oncogenic programs and restores tumor suppressor function in HGG. Despite the phenotypic response being largely additive, the consistent efficacy and associated transcriptomic shifts support its therapeutic potential. Furthermore, the identification of post-treatment gene signatures may facilitate the development of predictive biomarkers to guide patient stratification. This study underscores the value of integrating functional drug response with transcriptomic analysis to uncover molecular vulnerabilities and inform precision treatment strategies in HGG. Citation Format: Yating Shen, Dexter Kai Hao Thng, Canh Quan Nguyen, Tuan Zea Tan, Bryce Wei Quan Tan, Lissa Hooi, Masturah Bte Mohd Abdul Rashid, Jhin Jieh Lim, Nagarjun Bolem, Nivedh Dinesh, Char Loo Tan, Yvonne Li En Ang, Chun Peng Goh, Shiong Wen Low, Vincent Diong Weng Nga, Tseng Tsai Yeo, Edward Kai-Hua Chow, Dean Ho, Andrea Li Ann Wong, Tan Boon Toh. Dual Inhibition of Protein Degradation and Nuclear Export Uncovers Molecular Dependencies in Gliomas abstract. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86 (13Suppl): Abstract nr LT06.
Shen et al. (Thu,) studied this question.