Summary: The mechanisms of osimertinib resistance have not been well characterized. We conducted next-generation sequencing to recognize novel resistance mechanism and used cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models to evaluate the anti-proliferative effects of aspirin in vivo and in vitro. We observed that PIK3CG mutations led to acquired resistance to osimertinib in a patient and further confirmed that both PIK3CG and PIK3CA mutations caused osimertinib resistance. Mechanistically, the expression of PI3Kγ or PI3Kα was up-regulated after PIK3CG or PIK3CA lentivirus transfection, respectively, and which can be effectively suppressed by aspirin. Lastly, our results from in vivo studies indicate that aspirin can reverse osimertinib resistance caused by PIK3CG or PIK3CA mutations in both CDX and PDX models. Herein, we first confirmed that mutations in PIK3CG can lead to resistance to osimertinib, and the combined therapy may be a strategy to reverse PIK3CG/PIK3CA mutation-induced osimertinib resistance.
