Role of antiapoptotic STAT3 and BCL-2 signaling in promoting lung tumor cells to survive against combined MET-/EGFR-targeted inhibitors.

Abstract

10644 Background: Epidermal growth factor receptor (EGFR) inhibitors in lung cancer are largely limited by the development of resistant disease that ultimately limits their clinical utility. Combined targeted therapy strategies using both MET and EGFR small molecular tyrosine kinase inhibitors (TKIs) are under preclinical and clinical investigation to enhance the therapeutic efficacy and to circumvent acquired EGFR TKI resistance in lung cancer. These combined therapeutic approaches are likely to have unique mechanisms of resistance. Methods: We investigated the effects of combined MET/EGFR TKI treatment on signal transducer and activator of transcription 3 (STAT3) and B-cell lymphoma protein 2 (BCL-2) family members in lung cancer cell lines and xenografts models that are resistant to EGFR inhibitors. Results: Activated STAT3 and BCL-2/BCL-XL induction were seen in lung tumor cells that survived targeted inhibition by MET kinase inhibitors (SU11274 and PHA665752), either alone or in combination with EGFR inhibitors. Using in vivo xenograft model with luciferase-expressing H1975 cells for bioluminescence imaging (BLI), we show that while the H1975 xenograft exhibited excellent imaging tumor response when treated with combined SU11274 (MET TKI) and erlotinib (EGFR TKI), activated P-STAT3[Y705] expression was evident in the residual microscopic tumor survivor cells within the treated xenograft. Interestingly, the resistant survivor tumor cells were located predominantly along the peripheral rind juxtaposing the host stroma. BCL-2 expression was also found induced in the tumor survivor cells during the course of targeted combined MET/EGFR inhibition in vivo. Conclusions: Results of our study support the role of activated STAT3, and its downstream transcriptional targets of the antiapoptotic BCL-2 family members as potential markers for tumor resistance against combined MET/EGFR targeted inhibitors in lung cancer. Further investigations to target the intrinsic apoptotic pathway with BCL-2 family inhibitors, which may overcome or prevent resistance against combined MET/EGFR TKIs, are warranted to impact on the long term outcome in lung cancer therapy. No significant financial relationships to disclose.