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Figure 2. Alternative bypass signaling mechanisms of osimertinib-acquired resistance in EGFR-mutated NSCLC and corresponding management strategies. Transmembrane receptors such as MET, HER2, and AXL, as well as downstream pathways including PI3K and RAS, may undergo mutation, fusion, or amplification, leading to resistance to osimertinib (Created with BioRender.com. https://BioRender.com/wr8kb92). EGFR: Epidermal growth factor receptor; MET: mesenchymal-epithelial transition factor; HER2: human epidermal growth factor receptor 2; AXL: AXL receptor tyrosine kinase; ALK: anaplastic lymphoma kinase; PI3K: phosphatidylinositol 3-kinase; AKT: protein kinase B; RAS: rat sarcoma viral oncogene homolog; RAF: rapidly accelerated fibrosarcoma; MEK: mitogen-activated protein kinase kinase; ERK: extracellular signal-regulated kinase; JAK: Janus kinase; STAT3: signal transducer and activator of transcription 3; EMT: epithelial-mesenchymal transition; NSCLC: non-small-cell lung cancer.