In conclusion, our data demonstrate that molecular mechanisms of resistance to EGFR-TKIs are significantly affected by inadequate drug exposures and the cellular genetic background, and provide the rationale for further studies validating the role of TGF-β1 as a potential target to overcome resistance to EGFR-TKIs and for developing therapeutic strategies aimed at mitigating tumor heterogeneity in NSCLC. Here, EGFR is linked to neoplasm.