KRAS-mutant non-small cell lung cancer (NSCLC) therapy based on tepotinib and omeprazole combination
Por:
Rosell, Rafael, Jantus-Lewintre, Eloisa, Cao, Peng, Cai, Xueting, Xing, Baojuan, Ito, Masaoki, Gomez-Vazquez, Jose Luis, Marco-Jordan, Mireia, Calabuig-Farinas, Silvia, Cardona, Andres Felipe, Codony-Servat, Jordi, Gonzalez, Jessica, Valencia-Clua, Kevin, Aguilar, Andres, Pedraz-Valdunciel, Carlos, Dantes, Zahra, Jain, Anisha, Chandan, S., Molina-Vila, Miguel Angel, Arrieta, Oscar, Ferrero, Macarena, Camps, Carlos, Gonzalez-Cao, Maria
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
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
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
Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Surg Oncol, Hiroshima,
Japan
Hosp Uni Bellvitge, Bellvitge Biomed Res Inst IDIBELL, Lhospitalet De
Llobregat, Spain
Univ Valencia, Dept Pathol, Valencia, Spain
Inst Res & Educ, Luis Carlos Sarmiento Angulo Canc Treatment & Res,
Bogota, Colombia
Hosp Quiron Dexeus Barcelona, Pangaea Oncol, Barcelona, Spain
Invitrocue, Barcelona, Spain
Invitrocue, Munich, Germany
JSS Acad Higher Educ & Res, Dept Microbiol, Mysuru, India
Natl Inst Cancerol INCAN, Mexico City, Mexico
Gen Univ Hosp Valencia, Med Oncol Dept, Valencia, Spain
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