EGFR/c-Met and mTOR signaling are predictors of survival in non-small cell lung cancer

Abstract

Background: EGFR/c-Met activation/amplification and co-expression, mTOR upregulation/activation, and Akt/Wnt signaling upregulation have been individually associated with more aggressive disease and characterized as potential prognostic markers for lung cancer patients. Methods: Tumors obtained from 109 participants with stage I–IV non-small cell lung cancer (NSCLC) were studied for EGFR/c-Met co-localization as well as for total and active forms of EGFR, c-Met, mTOR, S6K, beta-catenin, and Axin2. Slides were graded by two independent blinded pathologists using a validated scoring system. Protein expression profile correlations were assessed using Pearson correlation and Spearman’s rho. Prognosis was assessed using Kaplan–Meier analysis. Results: Protein expression profile analysis revealed significant correlations between EGFR/p-EGFR ( p = 0.0412) and p-mTOR/S6K ( p = 0.0044). Co-localization of p-EGFR/p-c-Met was associated with increased p-mTOR ( p = 0.0006), S6K ( p = 0.0018), and p-S6K ( p < 0.0001) expression. In contrast, active beta-catenin was not positively correlated with EGFR/c-Met nor any activated proteins. Axin2, a negative regulator of the Wnt pathway, was correlated with EGFR, p-EGFR, p-mTOR, p-S6K, EGFR/c-Met co-localization, and p-EGFR/p-c-Met co-localization (all p-values <0.03). Kaplan–Meier analysis revealed shorter median survival in participants with high expression of Axin2, total beta-catenin, total/p-S6K, total/p-mTOR, EGFR, and EGFR/c-Met co-localization compared with low expression. After controlling for stage of disease at diagnosis, subjects with late-stage disease demonstrated shorter median survival when exhibiting high co-expression of EGFR/c-Met (8.1 month versus 22.3 month, p = 0.050), mTOR (6.7 month versus 22.3 month, p = 0.002), and p-mTOR (8.1 month versus 25.4 month, p = 0.004) compared with low levels. Conclusions: These findings suggest that increased EGFR/c-Met signaling is correlated with upregulated mTOR/S6K signaling, which may in turn be associated with shorter median survival in late-stage NSCLC.

Afatinib in Untreated Stage IIIB/IV Lung Adenocarcinoma with Major Uncommon Epidermal Growth Factor Receptor (EGFR) Mutations (G719X/L861Q/S768I): A Multicenter Observational Study in Taiwan

“…In addition, the primary EGFR mutations in this study were detected by polymerase chain reaction (PCR)-based single gene sequencing and not by next-generation sequencing (NGS), which can detect more known and unknown genetic alterations. Some genetic mutations, such as those in MET and TP53, concurrently appear in EGFR-mutated NSCLC and negatively alter the efficacy of EGFR-TKI therapy and survival [ 44 , 48 , 49 ]. We did not find other unknown concurrent genetic alterations that affect the efficacy of afatinib therapy.…”

The clinicopathological and prognostic significance of mTOR and p-mTOR expression in patients with non-small cell lung cancer: A meta-analysis

“…1263 pieces of relevant literature were retrieved; 178 duplicate articles were removed; 119 articles were checked automatically using Endnote software and 59 articles were checked manually; By reading the title and abstract, 1036 articles, including reviews, case reports, animal experiments, and unrelated articles, were removed; By carefully reading the full text, 21 articles were eliminated, including 1 article not written in English or Chinese, 3 reviews and conference abstracts, 7 repeated data studies, 8 studies that did not provide mTOR/p-mTOR positive expression rate or prognosis-related data, and 2 studies that did not directly report HR value and its 95% CI but only gave K-M survival curve, [50,51] and a total of 28 studies were determined to be included. [52–79] Figure 1 shows the flowchart of the literature search.…”

Arsenic Inhibits Proliferation and Induces Autophagy of Tumor Cells in Pleural Effusion of Patients with Non-Small Cell Lung Cancer Expressing EGFR with or without Mutations via PI3K/AKT/mTOR Pathway

“…Furthermore, mTORC1 is able to phosphorylate the transcription initiation factor eIF4E-binding proteins (4E-BPs), and the phosphorylated 4E-BPs dissociated from eIF4E, and these events promote the entry of eIF4E into the transcription complex for transcription [ 36 ]. Recent studies demonstrated that the high expression of pAKT, pmTOR, and peIF4E can be detected in some patients with NSCLC, especially in those with lymph node metastasis, confirming that the high expression of these proteins is positively correlated with the degree of tumor malignancy and with poor prognosis [ 36 , 37 ]. In this study, we found that arsenic down-regulated PI3K and PTEN ( Figure 4 ), which led to the inhibition of AKT phosphorylation and ultimately led to the inhibition of cell growth, proliferation, and invasion.…”