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Javier Alcacer



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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-31 - Chemokine Receptor CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC (ID 2817)

      10:15 - 18:15  |  Author(s): Javier Alcacer

      • Abstract

      Background

      Activating EGFR mutations in NSCLC confer sensitivity to reversible EGFR TKIs, including gefitinib and erlotinib. Despite promising initial response, acquired resistance develops mediated by the emergence of the secondary T790M mutation or by focal amplification of MET. An epithelial­to­mesenchymal transition (EMT) is clinically linked to NSCLCs with acquired EGFR TKI resistance. The exact mechanisms of EGFR TKI resistance with EMT phenotype remain elusive.

      Method

      We have engineered EGFR­mutated NSCLC cell lines with a mesenchymal phenotype by stably depleting E­Cadherin, overexpressing Snail, or chronically exposing the cells to TGFβ1. The resulting mesenchymal cells are resistant to EGFR TKIs. We employed genomic analyses to identify commonly activated oncogenic drivers that maintain signaling pathways upon EGFR inhibition. We also used EGFR­mutated HCC4006 NSCLC cells grown resistant to gefitinib that developed a mesenchymal phenotype (HCC4006Ge­R). To extend our findings to in vivo, we have utilized matched pre- and post-EGFR TKI treatment samples from NSCLC patient and mouse models of acquired EGFR TKI resistance to test if our approach using these cell lines is instructive.

      Result

      We discovered that an atypical GPCR, C­X­C chemokine receptor type 7 (CXCR7), is commonly overexpressed in the cell line models of EGFR TKI resistance with a mesenchymal phenotype. The murine tumors driven by human EGFR exon19 deletion/T790M (TD) with acquired resistance to WZ4002 present mesenchymal phenotype and overexpress CXCR7. 50% of NSCLC patients harboring an EGFR kinase domain mutation who progressed on EGFR inhibitors showed an increase in CXCR7 expression. Using the cell line model of EGFR TKI acquired resistance with a mesenchymal phenotype, we find that CXCR7 activates the MAPK-ERK pathway via b-arrestin. Depletion of CXCR7 abrogates the MAPK pathway and significantly attenuated EGFR TKI resistance in the cells with a mesenchymal phenotype. In the long term, the depletion of CXCR7 resulted in mesenchymal to epithelial transition. Ectopic overexpression of CXCR7 in HCC4006 cells was sufficient in activation of ERK1/2 for the generation of EGFR TKI resistant cells. Furthermore, CXCL12 stimulation resulted in an increase in ERK phosphorylation while EGFR was inhibited in HCC4006Ge-R cells. Similarly, we found we found CXCL12 expression is elevated in patient samples with increased CXCR7 expression.

      Conclusion

      Taken together, we discovered that the CXCR7-CXCL12 signaling axis is necessary and sufficient for the maintenance of EGFR TKI resistance with mesenchymal phenotype and CXCR7 inhibition could significantly delay and prevent the emergence of acquired EGFR TKI resistance in EGFR mutant NSCLC.