Clinical significance of TP53 alterations in advanced NSCLC patients treated with EGFR, ALK and ROS1 tyrosine kinase inhibitors: An update

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.

Unraveling the Potential of ALK-Targeted Therapies in Non-Small Cell Lung Cancer: Comprehensive Insights and Future Directions

“…However, considering the link between TP53 mutations in NSCLC and diminished responsiveness to EGFR, ALK, and ROS1 targeted therapy in diverse studies, the discourse delved into the influence of TP53 mutations on treatment resistance. While assessing TP53 mutation status seems logical for patient stratification in clinical decision-making, the precise clinical significance of TP53 co-mutations in ALK+ NSCLC remains unclear [153].…”

Lung cancer biomarkers: Raising the clinical value of the classical and the new ones

“…As accurate ctDNA diagnostics depends strongly on standardized preanalytical sample handling, Bronkhorst et al [42] provide a useful pocket companion to cell-free DNA (cfDNA) preanalytics. Finally, Moes-Sosnowska et al [43] give an update on the clinical significance of TP53 alterations in advanced NSCLC patients treated with EGFR, ALK and ROS1 tyrosine kinase inhibitors.…”

New Generations of Tyrosine Kinase Inhibitors in Treating NSCLC with Oncogene Addiction: Strengths and Limitations

“…Additionally, the optimal sequencing of these agents and their integration into the treatment landscape of NSCLC requires careful consideration (Figure 1). The identification of predictive biomarkers and the management of adverse effects associated with TKI therapy are also areas of active investigation [10].…”

“…Additionally, the optimal sequencing of these agents and their integration into the treatment landscape of NSCLC requires careful consideration (Figure 1). The identification of predictive biomarkers and the management of adverse effects associated with TKI therapy are also areas of active investigation [10]. This review manuscript will provide a thorough analysis of the strengths and limitations associated with the use of TKIs in NSCLC with oncogene addiction.…”