Fig. 2

Schematic diagram explaining mechanisms of acquired resistance to EGFR TKIs. A. Mutant EGFR confers resistance to binding of TKIs to the tyrosine kinase domain of EGFR. This activates downstream signaling pathways such as the PI3K-AKT pathway, JAK-STAT pathway, RAS pathway and ERK-MAPK pathway. B. Overexpression of HGF causes TKI-resistance that activates downstream signaling of the PI3K-AKT pathway, JAK-STAT pathway, RAS pathway and ERK-MAPK pathway. The above pathways result in cell proliferation, cell migration, invasion, and metastasis, that in turn cause the release of CTCs, ctDNA, miRNA, lncRNA, exosomes and TEPs into the bloodstream. Liquid biopsy helps examine these biomarkers and assess the type of mutation. Created with BioRender.com (Agreement number: XF237SHT72). Abbreviations: EGFR: Epidermal growth factor receptor; TK: Tyrosine kinase; CTCs: Circulating tumor cells; ctDNA: Circulating tumor DNA; miRNA: Micro RNA; lncRNA: Long non-coding RNA; TEPs: Tumor educated platelets; mTOR: Mammalian target of rapamycin; AKT: V-akt murine thymoma viral oncogene homolog; PI3K: Phosphoinositide 3-kinase; STAT3: Signal transducer and activator of transcription 3; JAK: Janus Activated Kinase; ERK: Extracellular-signal-regulated kinase; MAPK: Mitogen-activated protein kinase; MEK: Mitogen-activated protein kinase kinase; RAF: Rapidly Accelerated Fibrosarcoma; RAS: Rat sarcoma virus; HGF: Hepatocyte growth factor; TKIs: Tyrosine kinase inhibitors; MET: Mesenchymal epithelial transition factor