CXCR7 reactivates ERK signaling to promote resistance to EGFR kinase inhibitors in NSCLC.

摘要: 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 TKI with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK-ERK pathway via β-arrestin. Depletion CXCR7 inhibited MAPK pathway, significantly attenuated resistance, and resulted mesenchymal-to-epithelial transition. overexpression was essential reactivation ERK1/2 for generation TKI-resistant persister cells. Many patients non-small cell lung cancer (NSCLC) harboring domain mutation, who progressed on inhibitors, demonstrated increased expression. These data suggest inhibition could considerably delay prevent emergence EGFR-mutant NSCLC. SIGNIFICANCE: Increased expression chemokine receptor constitutes mechanism to through ERK signaling.