Crosstalk to stromal fibroblasts induces resistance of lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors.

摘要: Purpose: Lung cancers with epidermal growth factor receptor (EGFR)–activating mutations show good clinical response to gefitinib and erlotinib, selective tyrosine kinase inhibitors (TKI) EGFR, but these tumors invariably develop drug resistance. Host stromal cells have been found a considerable effect on the behavior of cancer cells. Little is known, however, about role host sensitivity TKIs. We therefore assessed crosstalk between lung harboring EGFR susceptibility EGFR-TKIs. Experimental Design: evaluated EGFR-activating mutations, PC-9 HCC827, when cocultured fibroblasts coinjected into severe combined immunodeficient mice. also examined fibroblast recruitment. Results: Both human cell lines primary cultured produced various levels hepatocyte (HGF). markedly recruited fibroblasts. The became resistant EGFR-TKIs in vitro HGF-producing Importantly, use plus anti-HGF antibody or HGF antagonist, NK4, successfully overcame fibroblast-induced EGFR-TKI resistance both vivo . Colocalization was detected xenograft mouse model patient specimens. Conclusions: These findings indicate that plays critical may be an ideal therapeutic target mutations. (Clin Cancer Res 2009;15(21):6630–8)