Sitravatinib combined with osimertinib overcomes acquired osimertinib resistance in NSCLC by targeting AXL and the PI3K/AKT/GSK3β signaling pathway

Abstract

The emergence of acquired resistance to osimertinib has emerged as a severe plight in the clinical management of patients with advanced harboring epidermal growth factor receptor mutations non-small cell lung (NSCLC). We comprehensively evaluated sitravatinib, an emerging multitarget tyrosine kinase inhibitor, for its potential to counter osimertinib resistance in NSCLC. The anti-tumor effectiveness of the combined administration of sitravatinib and osimertinib was evaluated in vitro using functional experiments, including cell viability, wound healing, and Transwell migration and invasion assays, together with an in vivo nude mouse xenograft model. Corresponding molecular mechanisms were further elucidated via RT-qPCR and Western blot analyses. Our findings revealed that this combination treatment resulted in markedly reinforced anti-tumor activity both in vitro and in vivo relative to single-agent administration. Mechanistic exploration revealed that sitravatinib overcomes resistance by suppressing the AXL and PI3K/AKT/GSK3β signaling cascades and reversing the epithelial–mesenchymal transition. Collectively, the current study offers preliminary proof that the putative efficacy and favorable safety profile of the sitravatinib–osimertinib combination in addressing acquired osimertinib resistance in NSCLC, potentially presenting a novel and promising therapeutic option for patients with clinical osimertinib resistance.