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Core Findings and Evidence Quality

This PeerJ study (published 11 Sep 2026) reports that esomeprazole (ESO; 0–120 mg/L) reduced AGS and HGC-27 cell viability in a dose- and time-dependent manner (CCK-8, 6–48 h), and at 80 mg/L for 24 h suppressed wound closure, Transwell migration/invasion, and protein expression of N-cadherin, MMP2, MMP9, and Vimentin Primary PeerJ paper, full-text evidence. EGF (50–100 ng/mL) enhanced migration/invasion independent of proliferation, and ESO reversed these EGF-driven changes with parallel reductions in p-EGFR (Tyr1068), p-AKT (Ser473), and p-mTOR (Ser2448). Combining ESO with afatinib (2 µM) outperformed either monotherapy across all endpoints.

Strengths: at least three independent replicates, two GC cell lines, consistent multi-assay convergence (CCK-8, wound healing, Transwell, western blot), publicly deposited data Figshare raw dataset for the study, and disclosed provincial funding without industry COI.

Weaknesses (authors partially acknowledge): (1) Mechanism is purely correlative — no EGFR/AKT/mTOR inhibitors, siRNA knockdown, or rescue experiments establish causality; (2) no in vivo xenograft or clinical data; (3) EGF lacked dose-dependence on migration, weakening the mechanistic narrative; (4) 80 mg/L ESO is far above clinically achievable plasma exposures (~0.5–2 µM range), raising translational relevance questions; (5) combination "synergy" was not formally quantified (no Bliss/Chou-Talalay analysis, no CI values reported); (6) only p-EGFR/AKT/mTOR were probed — total protein levels and upstream V-ATPase/pH effects were not assessed, leaving the authors' prior V-ATPase/EGFR-downregulation hypothesis Prior work by Du et al. linking ESO to EGFR downregulation untested here.

What would falsify the central claim: if ESO's anti-migratory effect persists when EGFR/AKT/mTOR is independently knocked down or rescued, the pathway attribution fails. Broader EGFR-trafficking literature (e.g., LDOC1 control of EGFR internalization and resistance) suggests additional untested mechanisms may be at play EGFR trafficking and resistance context (IJMS 2024).

Author Reviews

 BGPT Paper Review

Study Novelty

PPI repurposing as anticancer agent and EGFR/AKT/mTOR pathway involvement are well-established themes; extending ESO to EGF-induced migration plus afatinib combination adds incremental, not groundbreaking, novelty.

Scientific Quality

Consistent multi-assay design with ≥3 replicates and two cell lines, but purely correlative mechanism, lack of synergy quantification, supraphysiologic ESO doses, and absence of in vivo data limit quality. AstraZeneca-supplied ESO is noted but declared non-conflicted.

Study Generality

Findings apply to two specific gastric cancer cell lines under one ESO dose (80 mg/L); pathway and drug class effects may generalize, but metastasis biology conclusions are cell-line and dose specific.

Study Usefulness

Provides a rationale for ESO-afatinib combination testing in gastric cancer, but therapeutic translation is blocked by the dose gap between in vitro and clinically tolerable esomeprazole exposures and absent efficacy/safety data in vivo.

Study Reproducibility

Methods are detailed (antibody catalog numbers, doses, time points, statistics in SPSS/GraphPad) and raw data deposited on Figshare; no preregistration or blinding reported, and combination-index analysis parameters are unspecified.

Explanatory Depth

Claims EGFR/AKT/mTOR mediation but provides no causal tests (inhibitors, knockdown, rescue, time-course phosphorylation kinetics); mechanism is inferred from correlative western blots only.