CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC.

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.

• Authors: Jeffrey H Becker, Yandi Gao, Margaret Soucheray, Ines Pulido, Eiki Kikuchi, María L Rodríguez, Rutu Gandhi, Aranzazu Lafuente-Sanchis, Miguel Aupí, Javier Alcácer Fernández-Coronado, Paloma Martín-Martorell, Antonio Cremades, José M Galbis-Caravajal, Javier Alcácer, Camilla L Christensen, Patricia Simms, Ashley Hess, Hajime Asahina, Michael P Kahle, Fatima Al-Shahrour, Jeffrey A Borgia, Agustín Lahoz, Amelia Insa, Oscar Juan, Pasi A Jänne, Kwok-Kin Wong, Julian Carretero, Takeshi Shimamura
• Journal: Cancer research (Cancer Res) Vol. 79 Issue 17 Pg. 4439-4452 (09 01 2019) ISSN: 1538-7445 [Electronic] United States
• PMID: 31273063 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• ACKR3 protein, human
• Protein Kinase Inhibitors
• Receptors, CXCR
• beta-Arrestins
• EGFR protein, human
• ErbB Receptors

Topics

• Animals
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, mortality)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (genetics)
• Epithelial-Mesenchymal Transition (genetics)
• ErbB Receptors (antagonists & inhibitors)
• Humans
• Lung Neoplasms (drug therapy, metabolism, mortality)
• MAP Kinase Signaling System (drug effects, genetics)
• Mice, Transgenic
• Mutation
• Neoplasms, Experimental (drug therapy, genetics)
• Protein Kinase Inhibitors (pharmacology)
• Receptors, CXCR (genetics, metabolism)
• beta-Arrestins (metabolism)