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Clinical significance of TP53 alterations in advanced NSCLC patients treated with EGFR, ALK and ROS1 tyrosine kinase
Joanna Moes-Sosnowska1, Adam Szpechcinski1, Joanna Chorostowska-Wynimko1
1Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.
Abstract:
The development of targeted therapies for non-small cell lung cancer (NSCLC), such as the epidermal growth factor receptor (EGFR), anaplastic lymphoma receptor tyrosine kinase (ALK), and ROS proto-oncogene 1 (ROS1), has improved patients' prognosis and significantly extended progression-free survival. However, it remains unclear why some patients do not benefit from the treatment as much or have a rapid disease progression. It is considered that, apart from the oncogenic driver gene, molecular alterations in a number of caretaker and gatekeeper genes significantly impact the efficacy of targeted therapies. The tumor protein 53 (TP53) gene is one of the most frequently mutated genes in NSCLC. To date, numerous studies have investigated the influence of various TP53 alterations on patient prognosis and responsiveness to therapies targeting EGFR, ALK, or ROS1. This review focuses on the latest data concerning the role of TP53 alterations as prognostic and/or predictive biomarkers for EGFR, ALK, and ROS1 tyrosine kinase inhibitors (TKIs) in advanced NSCLC patients. Since the presence of TP53 mutations in NSCLC has been linked to its decreased responsiveness to EGFR, ALK, and ROS1 targeted therapy in most of the referenced studies, the review also discusses the impact of TP53 mutations on treatment resistance. It seems plausible that assessing the TP53 mutation status could aid in patient stratification for optimal clinical decision-making. However, drawing meaningful conclusions about the clinical value of the TP53 co-mutations in EGFR-, ALK- or ROS1-positive NSCLC is hampered mainly by an insufficient knowledge regarding the functional consequences of the TP53 alterations. The integration of next-generation sequencing into the routine molecular diagnostics of cancer patients will facilitate the detection and identification of targetable genetic alterations along with co-occurring TP53 variants. This advancement holds the potential to accelerate understanding of the biological and clinical role of p53 in targeted therapies for NSCLC.
Insights
TP53 mutations in non-small cell lung cancer (NSCLC) may reduce patient response to targeted therapies like EGFR, ALK, and ROS1 inhibitors. Assessing TP53 status could improve treatment decisions for advanced NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Targeted therapies for non-small cell lung cancer (NSCLC) show promise, but patient response varies.
- Tumor protein 53 (TP53) gene mutations are common in NSCLC and may influence treatment efficacy.
- Understanding TP53's role is crucial for improving outcomes in advanced NSCLC.
Approach:
- This review synthesizes current data on TP53 alterations as biomarkers for targeted therapies in NSCLC.
- It examines the impact of TP53 mutations on patient prognosis and response to EGFR, ALK, and ROS1 inhibitors.
- The review discusses TP53's role in treatment resistance and potential clinical applications.
Key Points:
- TP53 mutations are frequently observed in NSCLC and are often associated with decreased responsiveness to EGFR, ALK, and ROS1 targeted therapies.
- Assessing TP53 mutation status may aid in stratifying patients for personalized treatment strategies.
- Further research into the functional consequences of TP53 alterations is needed to fully elucidate their clinical significance.
Conclusions:
- TP53 alterations represent a significant factor influencing the efficacy of targeted therapies in NSCLC.
- Integrating TP53 mutation status assessment into routine diagnostics can enhance clinical decision-making for advanced NSCLC patients.
- Next-generation sequencing advancements will facilitate the identification of TP53 variants, accelerating research into their role in targeted therapy response.
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