Abstract
Simple SummaryNon-Small-Cell Lung Cancer (NSCLC) is the primary cause of cancer-related death worldwide. Patients carrying Epidermal Growth Factor Receptor (EGFR) mutations usually benefit from targeted therapy treatment. Nonetheless, primary or acquired resistance mechanisms lead to treatment discontinuation and disease progression. Tumor protein 53 (TP53) mutations are the most common mutations in NSCLC, and several reports highlighted a role for these mutations in influencing prognosis and responsiveness to EGFR targeted therapy. In this review, we discuss the emerging data about the role of TP53 in predicting EGFR mutated NSCLC patients’ prognosis and responsiveness to targeted 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 (TP53) gene is the most frequently mutated gene in cancer, including NSCLC. TP53 mutations are able to induce carcinogenesis, tumor development and resistance to therapy, influencing patient prognosis and responsiveness to therapy. TP53 mutants present in different forms, suggesting that different gene alterations confer specific acquired protein functions. In recent years, many associations between different TP53 mutations and responses to Epidermal Growth Factor Receptor (EGFR) targeted therapy in NSCLC patients have been found. In this review, we discuss the current landscape concerning the role of TP53 mutants to guide primary and acquired resistance to Tyrosine-Kinase Inhibitors (TKIs) EGFR-directed, investigating the possible mechanisms of TP53 mutants within the cellular compartments. We also discuss the role of the TP53 mutations in predicting the response to targeted therapy with EGFR-TKIs, as a possible biomarker to guide patient stratification for treatment.
Highlights
Lung cancer (LC) is the main cause of cancer-related death worldwide [1]
We focus on the relation between Tumor protein 53 (TP53) mutations and Epidermal Growth Factor Receptor (EGFR)-mutated Non-Small-Cell Lung Cancer (NSCLC) subtype, discussing the achieved results on the role of such mutations in predicting responsiveness to Tyrosine-Kinase Inhibitors (TKIs)
Considering that patients with EGFR exon 19 deletions usually have a major benefit from first-line EGFR-TKIs compared to other EGFR mutations, it has been reported that TP53 mutations are able to mainly affect the objective response rate (ORR) and progression-free survival (PFS) of this subgroup of patients [114,133,134,135]
Summary
NonSmall Cell Lung Cancer (NSCLC), the most common LC histology, is a heterogeneous malignancy comprising molecular subtypes for which targeted agents are available in clinical practice [2]. Epidermal Growth Factor Receptor (EGFR) is the most common altered targetable gene in NSCLC, and its mutations Gene alterations affecting TP53 are proved to be a strong prognostic factor for NSCLC [5], and recent reports indicate a role for these mutations in predicting EGFR-mutated NSCLC patients responsiveness to TKIs. In this review, we focus on the relation between TP53 mutations and EGFR-mutated NSCLC subtype, discussing the achieved results on the role of such mutations in predicting responsiveness to TKIs. We explore possible cellular mechanisms that TP53 mutants activate to guide the resistance to therapy and discuss the emerging data on the role of these gene mutations for a possible patient stratification for EGFR-mutated patients. We discuss the classification systems proposed to date, as it has been demonstrated that different mutations confer different characteristics to the cancer cell
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