Osimertinib induces paraptosis and TRIP13 confers resistance in glioblastoma cells

Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor that has been evaluated in glioblastoma (GBM) in pre-clinical and clinical trials. However, the precise mechanism whereby Osimertinib induces GBM cell death as well as the underlying resistance mechanism to Osimertinibremain unclear. Here we show that Osimertinib induced 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. In addition, apoptosis or autophagy was not responsible for Osimertinib-induced cell death. RNA-seq analysis revealed that ER stress was the mostly deregulated pathway upon Osimertinib exposure. Consistently, pharmacologically targeting the PERK-eIF2α axis impaired Osimertinib-induced paraptosis. Noteworthy, we show that the expression of thyroid receptor-interacting protein 13 (TRIP13), an AAA+ATPase, alleviated Osimertinib-triggered paraptosis, thus conferring resistance. Intriguingly, an AKT inhibitor MK-2206 downregulated TRIP13 abundance and synergized with Osimertinib to suppress TRIP13-high GBM cell growth in vitro and in vivo. Thus, this study reveals a novel mechanism of action associated with the anti-GBM effects of Osimertinib, which involves ER stress-regulated paraptosis. Furthermore, we identify a TRIP13-driven resistance mechanism against Osimeritinib in GBM and offer a MK-2206-based combination strategy to overcome such resistance.