The three major, clinically relevant mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR mutant lung cancer are a second mutation in the EGFR gene (T790M), Met amplification, and increased expression of hepatocyte growth factor (HGF). Heat shock protein90 (Hsp90) is a 90kDa molecular chaperone for proteins that include EGFR, Met and EML4-ALK. Hsp90 inhibitors have been reported to reverse resistance to EGFR-TKIs caused by EGFR T790M mutation and Met amplification. Here, we determined whether inhibition of Hsp90 could overcome HGF-triggered EGFR-TKI resistance in EGFR mutant lung cancer cells. EGFR-TKI erlotinib inhibited the growth of PC-9, HCC827, and Ma-1 cells, with deletions in exon19 of EGFR, but not HGF-gene transfected Ma-1 (Ma-1/HGF) cells and H1975 cells, which contain the EGFR L858R and T790M mutations, respectively. Erlotinib also did not inhibit the growth of PC-9 and Ma-1 cells in the presence of HGF. However, an Hsp90 inhibitor, 17-DMAG, induced apoptosis and markedly inhibited the growth of these cell lines, even in the presence of HGF. This inhibition by 17-DMAG was associated with decreased expression of EGFR and Met, thereby decreasing Akt phosphorylation in tumor cells. In an in vivo model of HGF-triggered erlotinib-resistance, using Ma-1/HGF cells, 17-DMAG markedly suppressed tumor growth by decreasing angiogenesis and increasing apoptosis. These results indicate that Hsp90 inhibitors may overcome HGF-triggered resistance to EGFR-TKIs and that the use of Hsp90 inhibitors may result in more successful treatment of EGFR mutant lung cancers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1907. doi:1538-7445.AM2012-1907