TP53 Co-Mutations in Advanced EGFR-Mutated Non–Small Cell Lung Cancer: Prognosis and Therapeutic Strategy for Cancer Therapy

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide. As the most prevalent molecular mutation subtypes in non-small cell lung cancer (NSCLC), EGFR-TKIs are currently a standard first-line therapy for targeting the mutated EGFR in advanced NSCLC patients. However, 20-30% of this subset of patients shows primary resistance to EGFR-TKIs. Patients with co-mutations of EGFR and several other genes have a poor response to EGFR-TKIs, whereas the prognostic and predictive significance of EGFR/TP53 co-mutation in NSCLC patients remains controversial. Meanwhile, little is known about how to choose an optimal therapeutic strategy for this subset of patients. Presently, no drugs targeting TP53 mutations are available on the market, and some p53 protein activators are in the early stage of clinical trials. A combination of EGFR-TKIs with antiangiogenic agents or chemotherapy or other agents might be a more appropriate strategy to tackle the problem. In this review, we describe the prognostic and predictive value of EGFR/TP53 co-mutation in NSCLC patients, investigate the mechanisms of this co-mutation affecting the response to EGFR-TKIs, and further explore optimal regimens effectively to prolong the survival time of the NSCLC patients harboring this co-mutation.

Estrone analogs as potential inhibitors targeting EGFR‐MAPK pathway in non‐small‐cell lung cancer

“…Also, there is no current research claiming that p53 mutations are solely the critical molecular drivers of wild‐type NSCLC. Rather many studies have reported that NSCLC patients (with mutant or wild‐type EGFR tumors) harboring p53 mutations generally have increased rates of resistance to chemotherapy or EGFR TKIs (Jung et al, 2021; Liu et al, 2022). Cell cycle analysis studies were performed and showed that a significant G1 phase cell cycle arrest (Figure 2) induced by MMA307 and MMA320 treatment against NCI‐H226 cells offers support to the idea that these compounds inhibit cell proliferation.…”

Clinicopathologic characteristics and diagnostic methods of RET rearrangement in Chinese non-small cell lung cancer patients

“…We also characterized the mutational profile of the RET-rearranged patients and found that TP53 was the most common concurrent alteration. Previous studies have suggested that TP53 concomitant mutations have a strong negative effect on the outcomes of patients with EGFRmutant (42)(43)(44)(45) and ALK-rearranged NSCLC (43,46,47). The poor prognostic effect of the TP53 mutation on tumors may be due to the loss of tumor inhibitory function and the elevated level of genomic instability (48).…”

Genomic heterogeneity at baseline is associated with T790M resistance mutations in EGFR‐mutated lung cancer treated with the first‐/second‐generation tyrosine kinase inhibitors

“…To identify biomarkers that predict the development of T790M resistance mutations, we evaluated a multitude of complex biomarkers based on the WES data of both patient groups (Figure 2). NSCLC is known to harbor TP53 comutations [30], which we identified belonging to pathogenic and likely pathogenic categories in 21 cases (54% of the cohort patients, 48% in T790Mpos, and 64% in T790Mneg), yet they did not display a significant difference between both groups (Figure 2 and supplementary material, Table S2). While there were several other mutations present in both groups, we did not identify statistically significant differences for any mutation between T790Mpos and T790Mneg cases (supplementary material, Table S3).…”