Abstract 204P
Background
Proton Pump Inhibitor-Induced Gut Dysbiosis has been demonstrated in previous studies and was associated with poor prognosis in patients received immunotherapies and chemotherapies. However, little is known about the influence of Proton Pump Inhibitor-Induced dysbiosis on efficacies of target therapies like epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). We conduct a study to elucidate the role of PPI related dysbiosis on EGFR-TKIs efficacies.
Methods
Female BALB/c Mice were raised in specific pathogen-free (SPF) conditions and treated for 14 days proton pump inhibitor, lansoprazole (5 mg/kg) or control. Microbial was tested using NGS with the computational analysis of targeted (16S rRNA hypervariable regions). BALB/c mice were implanted with 5 × 106 H1975 NSCLC subcutaneously and treated orally when tumors reached 20 to 35 mm2 in size with EGFR-TKIs, Osimertinib (1 mg/kg/day). Feces were cultured on 5% sheep blood enriched Columbia Agar for aerobic and anaerobic conditions, respectively.
Results
Our study revealed PPI impaired TKI effectiveness in H1975 xenografts mice models (tumor fold change, with vs. without PPI: 28.1 vs. 7.4, p = 0.043). The feces culturomic analyses revealed Clostridiales vadin BB60 group was more abundances in xenogeneic EGFR-TKIs mice treated with PPI than without. The optimal cut-off point of relative abondance of operational taxonomic units (OTU) for Clostridiales vadin BB60 group determined by the ROC curve was 10.9%, p = 0.046. Mice with high abundance of Clostridiales vadin BB60 group had higher D17 tumor volume fold change (high vs low abundance of Clostridiales vadin BB60 group: 34.0 vs. 8.1, p = 0.025). Another taxa lactobacillus was more abundances in xenogeneic EGFR-TKIs treated mice with PPI than without. The optimal cut-off point of relative abondance of operational taxonomic units (OTU) for lactobacillus determined by the ROC was 0.3%, p < 0.001. Mice with high abundance of lactobacillus had higher D17 tumor volume fold change than mice with low abundance (tumor fold change 43.6 vs. 9.1, p = 0.04) by Mann-Whitney test.
Conclusions
Our study revealed PPI related dysbiosis are associated with poor EGFR-TKIs response in H1975 xenografts Mice.
Clinical trial identification
The Institutional Animal Care and Use Committee approved animal operative and experimental processes in Kaohsiung Chang Gung Memorial Hospital (Affidavit No. 2020030503).
Legal entity responsible for the study
The authors.
Funding
Kaohsiung Chang Gung Memorial Hospital.
Disclosure
All authors have declared no conflicts of interest.