In summary, our study yields three interesting observations: firstly, BRG1 status dictates the response to EGFR-TKIs in NSCLC cells that are wild-type for EGFR; secondly, resistance to EGFR-TKIs is partially mediated by pAKT(Ser473)–EGFR complex formation; thirdly, NSCLC harboring mt-BRG1/wt-EGFR may benefit from AKT-targeted therapy instead of EGFR-TKI therapy. Here, SMARCA4 is linked to non-small cell lung carcinoma.