The Role of TP53 Mutations in EGFR-Mutated Non-Small-Cell Lung Cancer: Clinical Significance and Implications for Therapy

Non-Small-Cell Lung Cancer (NSCLC) is the primary cause of cancer-related death worldwide. Oncogene-addicted patients usually benefit from targeted therapy, but primary and acquired resistance mechanisms inevitably occur. Tumor protein 53 (<i>TP53</i>) gene is the most frequently mutated gene in cancer, including NSCLC. <i>TP53</i> mutations are able to induce carcinogenesis, tumor development and resistance to therapy, influencing patient prognosis and responsiveness to therapy. <i>TP53</i> mutants present in different forms, suggesting that different gene alterations confer specific acquired protein functions. In recent years, many associations between different <i>TP53</i> mutations and responses to Epidermal Growth Factor Receptor (<i>EGFR</i>) targeted therapy in NSCLC patients have been found. In this review, we discuss the current landscape concerning the role of <i>TP53</i> mutants to guide primary and acquired resistance to Tyrosine-Kinase Inhibitors (TKIs) <i>EGFR</i>-directed, investigating the possible mechanisms of <i>TP53</i> mutants within the cellular compartments. We also discuss the role of the <i>TP53</i> mutations in predicting the response to targeted therapy with EGFR-TKIs, as a possible biomarker to guide patient stratification for treatment.