In our current study, overexpression of HOTAIR induces gefitinib resistance in lung cancer cells through inhibition of p16 and p21 gene expression, where HOTAIR may silence the p16 and p21 genes thereby promoting the expression of CDK4, CDK6, E2F1, and CyclinD1 to accelerate cell cycle progress in drug-resistant lung cancer cells. Here, CDK4 is linked to lung cancer.