Osimertinib induces paraptosis and TRIP13 confers resistance in glioblastoma cells

• Published in: Cell death discovery 2023-09, Vol.9 (1), p.333-333, Article 333
• Main Authors: Hu, Lulu, Shi, Ji, Shen, Dachuan, Zhai, Xingyue, Liang, Dapeng, Wang, Jing, Xie, Chunrui, Xia, Zhiyu, Cui, Jing, Liu, Feng, Du, Sha, Meng, Songshu, Piao, Haozhe
• Format: Article
• Language: English
• Subjects: 631/67/1059/2326; 631/80/82/23; AKT protein; Apoptosis; Autophagy; Biochemistry; Biomedical and Life Sciences; Brain cancer; Cell Biology; Cell Cycle Analysis; Cell death; Clinical trials; Down-regulation; Endoplasmic reticulum; Glioblastoma; Glioblastoma cells; Kinases; Life Sciences; Protein-tyrosine kinase receptors; Stem Cells; Targeted cancer therapy; Vacuoles
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-023-01632-6

The efficacy of osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, has been evaluated in glioblastoma (GBM) through preclinical and clinical trials. However, the underlying mechanism of osimertinib-induced GBM cell death and the underlying resistance mechanism to osimertinib remains unclear. Here, we demonstrate that Osimertinib induces paraptosis in GBM cells, as evidenced by the formation of cytoplasmic vacuoles, accumulation of ubiquitinated proteins, and upregulation of endoplasmic reticulum (ER) stress markers like CHOP. Additionally, neither apoptosis nor autophagy was involved in the osimertinib-induced cell death. RNAseq analysis revealed ER stress was the most significantly downregulated pathway upon exposure to osimertinib. Consistently, pharmacologically targeting the PERK-eIF2α axis impaired osimertinib-induced paraptosis. Notably, we show that the expression of thyroid receptor-interacting protein 13 (TRIP13), an AAA+ATPase, alleviated osimertinib-triggered paraptosis, thus conferring resistance. Intriguingly, MK-2206, an AKT inhibitor, downregulated TRIP13 levels and synergized with Osimertinib to suppress TRIP13-induced high GBM cell growth in vitro and in vivo. Together, our findings reveal a novel mechanism of action associated with the anti-GBM effects of osimertinib involving ER stress-regulated paraptosis. Furthermore, we identify a TRIP13-driven resistance mechanism against Osimertinib in GBM and offer a combination strategy using MK-2206 to overcome such resistance.