Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: a meta-analysis
Abstract:Background
The prognostic significance of TP53 concurrent mutations in patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)- mutated advanced non–small-cell lung cancer (NSCLC) who received EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs based targeted therapy remains controversial. Therefore, the present meta-analysis was performed to investigate the association between TP53 concurrent mutations and prognosis of patients with advanced NSCLC undergoing EGFR-TKIs or ALK… Show more
“…Given the above analyses of prognostic characteristics of multiple genes in lung cancer, we conclude that the EGFR + TP53 mutation subtype indicates a poorer prognosis than the EGFR mutation and multiple gene mutation subtypes, but there is no significant prognosis difference between the EGFR mutation and multiple gene mutation subtypes. This observation is in line with recent clinical outcome studies on non-small cell lung cancer with concurrent EGFR and TP53 mutations ( Hou et al., 2019 ; Jiao et al., 2018 ; Qin et al., 2020 ). Figure 4 Expression of differentially expressed prognostic genes and pairwise comparison among subtypes Unfavorable and favorable prognostic genes are shown in the left and right panels, respectively.…”
Section: Resultssupporting
confidence: 89%
“…Integrating multiple known lung-cancer-related prognostic gene expressions to infer the prognosis, we showed that the EGFR + TP53 mutation subtype has poorer prognosis than other subtypes, which is consistent with studies showing that patients harboring the EGFR and TP53 co-mutation have worse prognosis than patients harboring EGFR mutation only ( Hou et al., 2019 ; Jiao et al., 2018 ; Qin et al., 2020 ). Notably, our approach for the analysis is quite different from studies that mainly adopt survival analysis.…”
Lung adenocarcinoma (LUAD) patients in East Asia predominantly harbor oncogenic EGFR mutations. However, there remains a limited understanding of the biological characteristics and therapeutic vulnerabilities of the concurrent mutations of EGFR and other genes in LUAD. Here, we performed comprehensive bioinformatics analyses on 88 treatment-naïve East Asian LUAD patients. Based on somatic mutation clustering, we identified three somatic mutation subtypes: EGFR + TP53 co-mutation, EGFR mutation, and multiple-gene mutation. A proteogenomic analysis among subtypes revealed varying degrees of dysregulation in cell-cycle-related and immune-related processes. An immune-characteristic analysis revealed higher PDL1 protein expression in the EGFR + TP53 co-mutation subtype than in the EGFR mutation subtype, which may affect the therapeutic efficacy of anti-PD-L1 therapy. Moreover, integrating known and potential therapeutic target analysis reveals therapeutic vulnerabilities of specific subtypes and nominates candidate biomarkers for therapeutic intervention. This study provides new biological insight and therapeutic opportunities with respect to EGFRmutant LUAD subtypes.
“…Given the above analyses of prognostic characteristics of multiple genes in lung cancer, we conclude that the EGFR + TP53 mutation subtype indicates a poorer prognosis than the EGFR mutation and multiple gene mutation subtypes, but there is no significant prognosis difference between the EGFR mutation and multiple gene mutation subtypes. This observation is in line with recent clinical outcome studies on non-small cell lung cancer with concurrent EGFR and TP53 mutations ( Hou et al., 2019 ; Jiao et al., 2018 ; Qin et al., 2020 ). Figure 4 Expression of differentially expressed prognostic genes and pairwise comparison among subtypes Unfavorable and favorable prognostic genes are shown in the left and right panels, respectively.…”
Section: Resultssupporting
confidence: 89%
“…Integrating multiple known lung-cancer-related prognostic gene expressions to infer the prognosis, we showed that the EGFR + TP53 mutation subtype has poorer prognosis than other subtypes, which is consistent with studies showing that patients harboring the EGFR and TP53 co-mutation have worse prognosis than patients harboring EGFR mutation only ( Hou et al., 2019 ; Jiao et al., 2018 ; Qin et al., 2020 ). Notably, our approach for the analysis is quite different from studies that mainly adopt survival analysis.…”
Lung adenocarcinoma (LUAD) patients in East Asia predominantly harbor oncogenic EGFR mutations. However, there remains a limited understanding of the biological characteristics and therapeutic vulnerabilities of the concurrent mutations of EGFR and other genes in LUAD. Here, we performed comprehensive bioinformatics analyses on 88 treatment-naïve East Asian LUAD patients. Based on somatic mutation clustering, we identified three somatic mutation subtypes: EGFR + TP53 co-mutation, EGFR mutation, and multiple-gene mutation. A proteogenomic analysis among subtypes revealed varying degrees of dysregulation in cell-cycle-related and immune-related processes. An immune-characteristic analysis revealed higher PDL1 protein expression in the EGFR + TP53 co-mutation subtype than in the EGFR mutation subtype, which may affect the therapeutic efficacy of anti-PD-L1 therapy. Moreover, integrating known and potential therapeutic target analysis reveals therapeutic vulnerabilities of specific subtypes and nominates candidate biomarkers for therapeutic intervention. This study provides new biological insight and therapeutic opportunities with respect to EGFRmutant LUAD subtypes.
“…Concurrent TP53 mutation is now considered a negative prognostic factor in patients with EGFR-mutated LUAD that receive EGFR-TKIs. 53 A Chinese report found that concurrent TP53 mutation was more prevalent among young patients. 15 Gene fusions such as ALK, ROS, and RET rearrangements, though uncommon, are among the most frequent gene alterations that can be targeted in lung cancer.…”
Section: Genomic Profiling In Aya With Lung Cancermentioning
Lung cancer in young patients is an uncommon and understudied entity that harbors distinctive epidemiological, clinic-demographic, and genomic features. We carried out a systematic review of genomic profiling in young patients with lung cancer from 2010 to 2020 in the main electronic databases and selected 23 manuscripts. Lung cancer in young patients occurs more frequently in women with adenocarcinoma histology and at more advanced stages. Some studies report higher oncogenic genomic alteration in this population, with higher anaplastic lymphoma kinase rearrangements, a distinct profile of epidermal growth factor receptor mutations, and other novel genomic alterations. Although still uncommon, the implementation of next-generation sequencing (NGS) has shed some light on germline genomic alterations associated with lung cancer in young patients. Although outcomes when compared with the older population are conflicting, the overall prognosis is still poor in this subset of patients and efforts to find targetable genomic alterations should be made to improve survival.
“…H2228 cells carry a TP53 mutation and a NFE2L2 (Nrf2) G31A gain-of-function mutation, which constitutively activates the Nrf2 signaling pathway. Both mutations are associated with low sensitivity to ALKi 7, 8, 21 . To confirm the dysregulation of the Nrf2 signaling pathway, we compared the expression of Nrf2 and its target genes at both the mRNA and protein level in H3122 and H2228 cells.…”
Section: Resultsmentioning
confidence: 99%
“…Mechanisms for intrinsic resistance are poorly understood, but have been proposed to relate to e.g. the precise ALK fusion variant 5 , or TP53 mutations which frequently co-occur with ALK rearrangements 6,7,8 . Among tumors that acquire resistance to crizotinib, about 30% exhibit ALK-dependent resistance mechanisms, particularly ALK mutations and/or amplification 9,10 .…”
For non-small cell lung cancer (NSCLC) patients with ALK-rearranged tumors, treatment with ALK inhibitors can improve outcomes. However, clinical resistance typically develops over time, and in the majority of cases resistance mechanisms are ALK-independent. We generated tumor cell cultures from multiple regions of an ALK-rearranged clinical tumor specimen, and deployed functional drug screens to identify modulators of resistance to ALK inhibitors. This identified a role for PI3Kβ and EGFR in regulating resistance to ALK inhibition. Furthermore, inhibition of ALK elicited activation of EGFR, and inhibition of PI3Kβ rescued EGFR-mediated ALK inhibitor resistance. In ALK-rearranged primary cultures, cell lines and in vivo xenograft models, combined inhibition of ALK and PI3Kβ prevented compensatory MAPK and PI3K-AKT pathway reactivation and selectively targeted the cancer cells. The combinatorial effect was seen even in the background of TP53 mutations and in epithelial-mesenchymal transformed cells. In conclusion, combinatorial ALK and PI3Kβ inhibitor treatment carries promise as a treatment for ALK-rearranged NSCLC.
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