Anticancer effects of an XPO1 inhibitor (selinexor) with sotorasib following omeprazole preconditioning in KRAS G12C-mutant non-small cell lung cancer cells in vitro and in a mouse tumor xenograft

Sep 23, 2026

Background: KRAS G12C-mutant advanced non-small cell lung cancer (NSCLC) is treated with KRAS G12C covalent inhibitors such as sotorasib, yet response rates and progression-free survival remain limited. Methods: KRAS G12C NSCLC cell lines, including sotorasib- and selinexor-resistant H2030, were treated with sotorasib plus selinexor after omeprazole pretreatment, assessing viability and protein expression; an H2030-derived xenograft model was also tested. Results: Omeprazole with the three-drug regimen nearly abolished colony formation, suppressing XPO1 and key downstream proteins and inhibiting xenograft growth without evident toxicity. Conclusions: XPO1 suppression requires combined therapy including omeprazole, supporting clinical exploration of XPO1 inhibition with KRAS inhibitors.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Abstract

Introduction

Methods

Results

Conclusions

Neoplasia 80 (2026) 101351 Contents lists available at ScienceDirect Neoplasia journal [homepage:](homepage: www.elsevier.com/locate/neo)[ www.elsevier.com/locate/neo](homepage: www.elsevier.com/locate/neo) Original Research Anticancer effects of an XPO1 inhibitor (selinexor) with sotorasib following omeprazole preconditioning in KRAS G12C-mutant non-small cell lung cancer cells in vitro and in a mouse tumor xenograft J`essica Gonz´alez a, Xueting Caib, Wenjing Diaob, Ga¨el Rou´e c, Kevin Val`encia-Clua a, Daniel Olmo-Gonz´alez d,e, María Gonz´alez-Caof, Anisha Jain g, Eloisa Jantus-Lewintre h,i,j, Ana Gim´enez-Capit´ank, Miguel Angel Molina-Vila k, Jordi Codony-Servata, Peng Cao b,l, Rafael Rosell f,* a FIOR Group, Germans Trias i Pujol Research Institute, Badalona (IGTP), Barcelona, Spain b Jiangsu Provincial Integrated Innovation Center of Hospital Preparations, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China c Lymphoma Translational Group, IJC Josep Carreras Leukaemia Research Institute, Badalona, Spain d FIOR Group, Dexeus University Hospital, Barcelona, Spain e University of Barcelona, Faculty of Biology, Department of Biochemistry and Molecular Biomedicine, Barcelona, Spain f Instituto Oncol´ogico Dr. Rosell (IOR), Dexeus University Hospital, Barcelona, Spain g Department of Microbiology, JSS Academy of Higher Education & Research, Mysuru, India h Instituto Interuniversitario de Investigaci´on de Reconocimiento Molecular y Desarrollo Tecnol´ogico (IDM), Universitat Polit`ecnica de Val`encia, Universitat de Val`encia, Valencia, Spain i Unidad Mixta UPV-CIPF de Investigaci´on en Mecanismos de EnfermedadesyNanomedicina, Universitat Polit`ecnica de Val`encia, Centro de Investigaci´on Príncipe Felipe, Valencia, Spain j Molecular Oncology Laboratory, General University Hospital Research Foundation, Valencia, Spain k Pangaea Oncology, Dexeus University Hospital, Barcelona, Spain l State Key Laboratory of Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, 210023, China A R T I C L E I N F O Keywords: KRAS G12C Non-small cell lung cancer Sotorasib Selinexor Exportin-1 (XPO1) MRAS A B S T R A C T Background: KRAS G12C-mutant advanced non-small cell lung cancer (NSCLC) is currently treated with KRAS G12C covalent inhibitors, such as sotorasib, or RAS (ON) G12-selective inhibitors; however, response rates and progression-free survival remain limited, with recurrence occurring in most patients. Although mechanisms of resistance in KRAS G12C cell lines are multifarious, they have been attributed to EGFR activation and Aurora kinase A (AURKA) signaling via Ras-related nuclear protein (Ran). Ran-GTP cooperates with Exportin-1 (XPO1), which has been identified as essential in KRAS-mutant NSCLC cells. Methods: KRAS G12C NSCLC cell lines, including H2030, which is resistant to sotorasib (KRAS G12C inhibitor) and selinexor (XPO1 inhibitor), were treated with sotorasib plus selinexor following pretreatment with omeprazole (a V-ATPase proton pump inhibitor) to assess effects on cell viability and protein expression. An in vivo study was also conducted using a KRAS G12C H2030 cell-derived tumor xenograft model. Results: The combination of omeprazole with sotorasib and selinexor almost completely suppressed colony formation in the KRAS G12C-mutant cell lines tested (NCI-H358, NCI-H23, NCI-H2030, and NCI-H358R). While sotorasib did not influence XPO1 protein expression in any of the cell lines, the combination of selinexor, omeprazole and sotorasib completely suppressed XPO1 expression, as well as AURKA, survivin, YAP1, MRAS, and other key proteins. In the H2030 xenograft model, tumor growth was significantly inhibited by treatment with the three-drug combination of omeprazole, sotorasib, and selinexor, with no apparent toxic side-effects or weight loss observed. * C

FAQs

What is the study’s main therapeutic hypothesis for KRAS G12C-mutant NSCLC?

The study evaluates whether combining an XPO1 inhibitor (selinexor) with sotorasib after omeprazole preconditioning suppresses XPO1 and related oncogenic proteins more effectively than sotorasib alone.

How were the anticancer effects assessed in vitro and in vivo?

In vitro, KRAS G12C NSCLC cell lines were treated with sotorasib plus selinexor following omeprazole pretreatment to measure viability and protein expression. In vivo, an H2030 cell-derived tumor xenograft model assessed tumor growth and tolerability.

What were the key findings about XPO1 suppression?

XPO1 protein suppression was not achieved with sotorasib alone. The combination of sotorasib, selinexor, and omeprazole abolished XPO1 expression and reduced multiple downstream proteins, while significantly inhibiting tumor growth in the xenograft model.

Sep 23, 2026

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