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RESEARCH PRODUCT
CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC
Ines PulidoJavier AlcácerJavier Alcácer Fernández-coronadoJulian CarreteroJosé M. Galbis-caravajalKwok-kin WongPatricia E. SimmsJeffrey H. BeckerJeffrey H. BeckerPaloma Martín-martorellRutu GandhiMargaret SoucherayMiguel AupiAránzazu Lafuente-sanchisAmelia InsaAgustín LahozAshley HessFatima Al-shahrourCamilla L. ChristensenMichael P. KahleYandi GaoJeffrey A. BorgiaOscar JuanMaria L. RodriguezHajime AsahinaAntonio CremadesEiki KikuchiPasi A. JänneTakeshi Shimamurasubject
0301 basic medicineMAPK/ERK pathwayCancer ResearchLung NeoplasmsDrug ResistanceDrug resistanceTransgenicMiceChemokine receptor0302 clinical medicineNeoplasmsCarcinoma Non-Small-Cell LungReceptorsMedicineNon-Small-Cell LungCXCRReceptorLungbeta-ArrestinsCancerEGFR inhibitorsTumorKinaseLung CancerErbB ReceptorsOncology5.1 Pharmaceuticals030220 oncology & carcinogenesisDevelopment of treatments and therapeutic interventionsTyrosine kinaseEpithelial-Mesenchymal TransitionMAP Kinase Signaling SystemOncology and CarcinogenesisMice TransgenicArticleCell LineExperimental03 medical and health sciencesClinical ResearchCell Line TumorAnimalsHumansOncology & CarcinogenesisProtein Kinase InhibitorsReceptors CXCRbusiness.industryCarcinomaNeoplasms Experimentalrespiratory tract diseases030104 developmental biologyProtein kinase domainDrug Resistance NeoplasmMutationCancer researchNeoplasmbusinessdescription
Abstract Although EGFR mutant–selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK–ERK pathway via β-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition. CXCR7 overexpression was essential in reactivation of ERK1/2 for the generation of EGFR TKI–resistant persister cells. Many patients with non–small cell lung cancer (NSCLC) harboring an EGFR kinase domain mutation, who progressed on EGFR inhibitors, demonstrated increased CXCR7 expression. These data suggest that CXCR7 inhibition could considerably delay and prevent the emergence of acquired EGFR TKI resistance in EGFR-mutant NSCLC. Significance: Increased expression of the chemokine receptor CXCR7 constitutes a mechanism of resistance to EGFR TKI in patients with non–small cell lung cancer through reactivation of ERK signaling.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-09-01 | Cancer Research |