In cytotoxicity experiments, whether RB1 was knocked down or ASCL1 was overexpressed, H1975 lung adenocarcinoma cells showed decreased drug sensitivity to TKIs, it shows that in TP53/RB1 co-mutated/inactivated LUAD cells, TKIs drug resistance begins, and TKIs drug resistance may further develop after neuroendocrine transformation. This evidence concerns the gene TP53 and lung adenocarcinoma.