Crosstalk to Stromal Fibroblasts Induces Resistance of Lung Cancer to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

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Purpose : Lung cancers with EGFR activating mutations show good clinical response to gefitinib and erlotinib, selective TKIs to epidermal growth factor receptor (EGFR), but these tumors invariably develop drug resistance. Host stromal cells have been found to have a considerable effect on the behavior of cancer cells. Little is known, however, about the role of host cells on the sensitivity of cancer cells to receptor tyrosine kinase inhibitors (TKIs). We have therefore assessed the effect of crosstalk between stromal cells and lung cancer cells harboring EGFR mutations on susceptibility to EGFR-TKIs.Experimental design : We evaluated the gefitinib sensitivity of lung cancer cells with EGFR activating muations, PC-9 and HCC827, when co-cultured with fibroblasts and co-injected into SCID mice. We also examined the effect of lung cancer cells to fibroblasts recruitment.Results : Both human fibroblast cell lines and primary cultured fibroblasts produced various level of HGF. Lung cancer cells markedly recruited fibroblasts. The lung cancer cells became resistant to EGFR-TKIs when co-cultured in vitro with HGF-producing fibroblasts and co-injected into SCID mice. Importantly, combined use of gefitinib plus anti-HGF antibody or the HGF antagonist, NK4 successfully overcame the fibroblast-induced EGFR-TKI resistance both in vitro and in vivo. Co-localization of fibroblasts and HGF was detected in both xenograft tumors in mouse model and lung cancer patient specimens.Conclusions : These findings indicate that crosstalk to stromal fibroblasts plays a critical role in lung cancer resistance to EGFR-TKIs and may be an ideal therapeutic target in lung cancer with EGFR activating mutations.