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Abstract Tumor heterogeneity is the major factor for inducing drug resistance. p53 is the major defender to maintain genomic stability, which is a high proportion mutated in most of the cancer types. In this study, we established in vivo animal models of gefitinib-induced drug-resistant lung cancer containing EGFR L858R and EGFR L858R *Tp53 +/− mice to explore the molecular mechanisms of drug resistance by studying the genomic integrity and global gene expression. The cellular morphology of the lung tumors between gefitinib-induced drug-resistant mice and drug-sensitive mice were very different. In addition, in drug-resistant mice, the expression of many cytoskeleton-related genes were changed, accompanied by decreased amounts of actin filaments and increased amounts of microtubule, indicating that significant cytoskeletal remodeling is induced in gefitinib-induced drug-resistant EGFR L858R and EGFR L858R *Tp53 +/− lung cancer mice. The gene expression profiles and involved pathways were different in gefitinib-sensitive, gefitinib-resistant and Tp53 +/− -mice. Increases in drug resistance and nuclear size (N/C ratio) were found in EGFR L858R *Tp53 +/− drug-resistant mice. Mutational hotspot regions for drug resistance via Tp53 +/+ - and Tp53 +/− -mediated pathways are located on chromosome 1 and chromosome 11, respectively, and are related to prognosis of lung cancer cohorts. This study not only builds up a gefitinib-induced drug-resistant EGFR L858R lung cancer animal model, but also provides a novel mutation profile in a Tp53 +/+ - or Tp53 +/− -mediated manner and induced cytoskeleton remodeling during drug resistance, which could contribute to the prevention of drug resistance during cancer therapy.