Rapidly Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in NSCLC Cell Lines through De-Repression of FGFR2 and FGFR3 Expression

摘要: Despite initial and sometimes dramatic responses of specific NSCLC tumors to EGFR TKIs, nearly all will develop resistance relapse. Gene expression analysis cell lines treated with the TKI, gefitinib, revealed increased levels FGFR2 FGFR3 mRNA. Analysis gefitinib action on a larger panel verified that is at mRNA protein level in which dominant for growth signaling, but not where signaling absent. A luciferase reporter containing 2.5 kilobases fgfr2 5′ flanking sequence was activated after treatment, indicating transcriptional regulation as contributing mechanism controlling expression. Induction well fgfr2-luc activity also observed Erbitux, an EGFR-specific monoclonal antibody. Moreover, inhibitors c-Src MEK stimulated similar degree suggesting these pathways may mediate EGFR-dependent repression FGFR3. Importantly, our studies demonstrate TKI-induced are capable mediating FGF2 FGF7 ERK activation FGF-stimulated transformed setting TKIs. In conclusion, this study highlights novel rapid acquired TKIs suggests treatment patients combinations FGFR be strategy enhance efficacy single inhibitors.