Journal Article

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

Ferrero, Macarena, Ito, Masaoki, Marco-Jordán, Mireia, Codony-Servat, Jordi, Aguilar, Andrés, Gonzalez, Jessica, Gomez-Vazquez, Jose Luis, Cai, Xueting, València-Clua, Kevin, Jantus-Lewintre, Eloisa, Pedraz-Valdunciel, Carlos, Jain, Anisha, Arrieta, Oscar, González-Cao, Maria, Chandan, S, Dantes, Zahra, Molina-Vila, Miguel Angel, Camps, Carlos, Rosell, Rafael, Calabuig-Fariñas, Silvia, Xing, Baojuan, Cardona, Andrés Felipe, Cao, Peng

2024

Overview

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

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adenocarcinoma / Adenosine triphosphatase / Animals / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Biomedical and Life Sciences / c-Met protein / Cancer / Cancer therapies / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - metabolism / Carcinoma, Non-Small-Cell Lung - pathology / Cell Biology / Cell Line, Tumor / Cell viability / Cells / Chemotherapy / Cytokines and Growth Factors / Dosage and administration / Down-regulation / Drug dosages / Drug resistance / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Drug therapy / Drug therapy, Combination / Ethylenediaminetetraacetic acid / Female / Gene expression / Genetic aspects / Glycolysis / H+-transporting ATPase / Health aspects / Hepatocyte growth factor / Humans / Immunotherapy / Inhibitor drugs / K-Ras protein / Kinases / Life Sciences / Low density lipoproteins / Lung cancer / Lung cancer, Non-small cell / Lung cancer, Small cell / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - pathology / MEK inhibitors / Mice / Mice, Nude / Mutants / Mutation / Non-small cell lung carcinoma / Omeprazole / Omeprazole - pharmacology / Omeprazole - therapeutic use / Pharmacology, Experimental / Phosphopyruvate hydratase / Phosphorylation / Physiological aspects / Piperazines / Piperidines / Protein-Ligand Interactions / Protein-tyrosine kinase receptors / Proteins / Proto-Oncogene Proteins c-met - antagonists & inhibitors / Proto-Oncogene Proteins c-met - genetics / Proto-Oncogene Proteins c-met - metabolism / Proto-Oncogene Proteins p21(ras) - genetics / Proton pump inhibitors / Pyridazines / Pyridines - pharmacology / Pyridines - therapeutic use / Pyridones / Pyrimidines - pharmacology / Pyrimidines - therapeutic use / Pyrimidinones - pharmacology / Pyrimidinones - therapeutic use / Receptor density / Receptors / Response rates / Ribosomal DNA / RNA / Small cell lung carcinoma / Testing / Triazines - pharmacology / Triazines - therapeutic use / Tumors / Tyrosine / Variance analysis / Xenograft Model Antitumor Assays / Xenografts