KRAS-mutant non-small cell lung cancer (NSCLC) therapy based on tepotinib and omeprazole combination
Por:
Rosell, R, Jantus-Lewintre, E, Cao, P, Cai, XT, Xing, BJ, Ito, M, Gomez-Vazquez, JL, Marco-Jordán, M, Calabuig-Fariñas, S, Cardona, AF, Codony-Servat, J, Gonzalez, J, València-Clua, K, Aguilar, A, Pedraz-Valdunciel, C, Dantes, Z, Jain, A, Chandan, S, Molina-Vila, MA, Arrieta, O, Ferrero, M, Camps, C and González-Cao, M
Publicada:
12 jun 2024
Resumen:
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.
Filiaciones:
:
Germans Trias & Pujol Res Inst IGTP, Barcelona, Spain
Hosp Quiron Dexeus Barcelona, IOR, Barcelona, Spain
Germans Trias & Pujol Hlth Sci Inst & Hosp IGTP, Lab Mol Biol, Cami Escoles S-N, Badalona 08916, Barcelona, Spain
Jantus-Lewintre, E:
Fdn Invest Hosp Gen Univ Valencia, Mol Oncol Lab, Valencia, Spain
Fdn Invest Hosp Gen Univ Valencia, Ctr Invest Principe Felipe, Trial Mixed Unit, Valencia, Spain
CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain
Univ Politecn Valencia, Dept Biotechnol, Cami Vera S-N, Valencia 46022, Spain
Univ Politecn Valencia, Ctr Invest Principe Felipe, Joint Unit Nanomed, Valencia, Spain
Cao, P:
Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Wester, Jiangsu Prov Med Innovat Ctr, Nanjing, Peoples R China
Nanjing Univ Chinese Med, State Key Lab Technol Chinese Med Pharmaceut Proc, Nanjing, Peoples R China
Wenzhou Med Univ, Quzhou Peoples Hosp, Quzhou Affiliated Hosp, Quzhou, Peoples R China
Shandong Acad Chinese Med, Jinan, Peoples R China
Cai, XT:
Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Wester, Jiangsu Prov Med Innovat Ctr, Nanjing, Peoples R China
Xing, BJ:
Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Wester, Jiangsu Prov Med Innovat Ctr, Nanjing, Peoples R China
Ito, M:
Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Surg Oncol, Hiroshima, Japan
:
Germans Trias & Pujol Res Inst IGTP, Barcelona, Spain
Hosp Uni Bellvitge, Bellvitge Biomed Res Inst IDIBELL, Lhospitalet De Llobregat, Spain
:
Germans Trias & Pujol Res Inst IGTP, Barcelona, Spain
Calabuig-Fariñas, S:
Fdn Invest Hosp Gen Univ Valencia, Mol Oncol Lab, Valencia, Spain
Fdn Invest Hosp Gen Univ Valencia, Ctr Invest Principe Felipe, Trial Mixed Unit, Valencia, Spain
CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain
Univ Valencia, Dept Pathol, Valencia, Spain
Cardona, AF:
Inst Res & Educ, Luis Carlos Sarmiento Angulo Canc Treatment & Res, Bogota, Colombia
Codony-Servat, J:
Germans Trias & Pujol Res Inst IGTP, Barcelona, Spain
Hosp Quiron Dexeus Barcelona, Pangaea Oncol, Barcelona, Spain
:
Germans Trias & Pujol Res Inst IGTP, Barcelona, Spain
València-Clua, K:
Germans Trias & Pujol Res Inst IGTP, Barcelona, Spain
Aguilar, A:
Hosp Quiron Dexeus Barcelona, IOR, Barcelona, Spain
Pedraz-Valdunciel, C:
Invitrocue, Barcelona, Spain
Dantes, Z:
Invitrocue, Munich, Germany
Jain, A:
JSS Acad Higher Educ & Res, Dept Microbiol, Mysuru, India
Chandan, S:
JSS Acad Higher Educ & Res, Dept Microbiol, Mysuru, India
Molina-Vila, MA:
Hosp Quiron Dexeus Barcelona, Pangaea Oncol, Barcelona, Spain
Arrieta, O:
Natl Inst Cancerol INCAN, Mexico City, Mexico
Ferrero, M:
Fdn Invest Hosp Gen Univ Valencia, Ctr Invest Principe Felipe, Trial Mixed Unit, Valencia, Spain
CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain
Camps, C:
Fdn Invest Hosp Gen Univ Valencia, Ctr Invest Principe Felipe, Trial Mixed Unit, Valencia, Spain
CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain
Gen Univ Hosp Valencia, Med Oncol Dept, Valencia, Spain
González-Cao, M:
Hosp Quiron Dexeus Barcelona, IOR, Barcelona, Spain
gold, Green Published
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