KRAS-mutant non-small cell lung cancer (NSCLC) therapy based on tepotinib and omeprazole combination

• DOI: 10.1186/s12964-024-01667-x
• Publication Date: 2024-06-12T10:02:08Z
• Authors: Rafael Rosell; Eloisa Jantus-Lew...; Peng Cao; Xueting Cai; Baojuan Xing; Masaoki Ito; Jose Luis Gomez-V...; Mireia Marco-Jordán; Silvia Calabuig-F...; Andrés Felipe Car...; Jordi Codony-Servat; Jessica Gonzalez; Kevin València-Clua; Andrés Aguilar; Carlos Pedraz-Val...; Zahra Dantes; Anisha Jain; S Chandan; Miguel Angel Moli...; Oscar Arrieta; Macarena Ferrero; Carlos Camps; Maria González-Cao
• Keywords: Trametinib; Dabrafenib

Abstract Background KRAS- mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS -G12C selective inhibitors, leading short median progression-free survival, overall survival. The MET receptor tyrosine kinase (c- ), the cognate of hepatocyte growth factor (HGF), was reported be overexpressed in -mutant cells tumor-growth anchorage-independent conditions. Methods Cell viability assay synergy analysis were carried out native, sotorasib trametinib-resistant NSCLC lines. Colony formation assays Western blot also performed. RNA isolation from tumors patients performed mRNA expression determined by real-time RT-qPCR. In vivo studies conducted (NCI-H358) cell-derived tumor xenograft model. Results Our research has shown promising activity omeprazole, V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, combination tepotinib G12C non-G12C lines, as well (AMG510, sotorasib) MEK (trametinib)-resistant Moreover, mouse model, omeprazole plus caused regression. We observed that these two drugs downregulates phosphorylation glycolytic enzyme enolase 1 (ENO1) low-density lipoprotein receptor-related protein (LRP) 5/6 H358 line, but not resistant, indicating effect could independent ENO1. addition, we examined probability recurrence-free survival 40 early adenocarcinoma mutation stratified levels. Significant differences according high levels expression. Hazard ratio (HR) 7.291 ( p = 0.014) for 3.742 0.052) Conclusions posit V-ATPase warrants further assessment non including those resistant covalent inhibitors.