KRAS-mutant non-small cell lung cancer (NSCLC) therapy based on tepotinib and omeprazole combination
Rosell, Rafael (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Jantus-Lewintre, E. (Centro Investigación Príncipe Felipe-Universitat Politècnica de Valencia)
Cao, P. (Shandong Academy of Chinese Medicine)
Cai, X. (Jiangsu Provincial Medical Innovation Center)
Xing, B. (Jiangsu Provincial Medical Innovation Center)
Ito, Masaoki (Hiroshima University)
Gomez-Vazquez, Jose Luis (Hospital Universitari de Bellvitge)
Marco-Jordán, Mireia (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Calabuig-Fariñas, S. (Universitat de València)
Cardona, A.F. (Luis Carlos Sarmiento Angulo Cancer Treatment and Research Center - CTIC)
Codony-Servat, Jordi (Hospital Quiron-Dexeus Barcelona)
Gonzalez, Jessica (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
València-Clua, Kevin (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Aguilar, A. (Hospital Quiron-Dexeus Barcelona)
Pedraz-Valdunciel, C. (Invitrocue)
Dantes, Z. (Invitrocue)
Jain, A. (JSS Academy of Higher Education & amp; Research)
Chandan, S. (JSS Academy of Higher Education & amp; Research)
Molina-Vila, M.A. (Hospital Quiron-Dexeus Barcelona)
Arrieta, O. (National Institute of Cancerology (INCAN))
Ferrero, M. (Centro de Investigación Biomédica en Red de Cáncer)
Camps, C. (Hospital General Universitari de València)
González-Cao, M. (Hospital Quiron-Dexeus Barcelona)
Universitat Autònoma de Barcelona

Date:	2024
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 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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Animals ; Antineoplastic Combined Chemotherapy Protocols ; Carcinoma, Non-Small-Cell Lung ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; Female ; Humans ; Lung Neoplasms ; Mice ; Mice, Nude ; Mutation ; Omeprazole ; Piperazines ; Piperidines ; Proto-Oncogene Proteins c-met ; Proto-Oncogene Proteins p21(ras) ; Pyridazines ; Pyridines ; Pyridones ; Pyrimidines ; Pyrimidinones ; Triazines ; Xenograft Model Antitumor Assays
Published in:	Cell communication and signaling, Vol. 22 Núm. 1 (june 2024) , p. 324, ISSN 1478-811X

DOI: 10.1186/s12964-024-01667-x
PMID: 38867255

15 p, 3.2 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Articles > Research articles
Articles > Published articles