Molecular mechanisms that support residual tumor cells in the early phase of EGFR tyrosine kinase inhibitor (TKI) monotherapy. Preexistence of a minor resistance subpopulation that will survive frontline EGFR TKI monotherapy (A), reversible drug-tolerant state mainly observed in cell line models (B), survival signaling from microenvironment (fibroblasts or dying cancer cells) (C), and role of poor vascularization (D) are shown. MET, MET proto-oncogene, receptor tyrosine kinase gene; IGF-1R, insulin-like growth factor 1 receptor; NF-κB, nuclear factor kappa light-chain enhancer of activated B cells; STAT3, signal transducer and activator of transcription 3; YAP, yes-associated protein; BIM, BCL2 like 11; HGF, human growth factor.