Although
epidermal growth factor receptor-
tyrosine kinase inhibitors (EGFR-TKIs) have been introduced for the treatment of
non-small cell lung cancer (NSCLC), the emergence of secondary T790M mutation in EGFR or amplification of the Met proto-oncogene restrain the clinical success of EGFR-TKIs. Since heat shock protein-90 (Hsp90) stabilizes various
oncoproteins including EGFR and c-Met, the inhibition of Hsp90 activity appears as a rational strategy to develop anticancer drugs. Despite preclinical efficacy of
geldanamycin-anasamycin (GA)-derivatives containing
benzoquinone moiety as Hsp90 inhibitors, the hepatotoxicity of these GA-derivatives restricts their therapeutic benefit. We have prepared WK-88 series of GA-derivatives, which lack the
benzoquinone moiety. In this study, we have examined the anticancer effects of
WK88-1 in Met-amplified- and
gefitinib-resistant (HCC827GR) NSCLC cells and its parental HCC827 cells. Treatment with
WK88-1 reduced the cell viability in both HCC827 and HCC827GR cells, which was associated with marked decrease in the constitutive expression of Hsp90 client
proteins, such as EGFR, ErbB2, ErbB3, Met and Akt. Moreover,
WK88-1 attenuated phosphorylation of these Hsp90 client
proteins and reduced the anchorage-independent growth of HCC827GR cells. Administration of
WK88-1 did not cause hepatotoxicity in animals and significantly reduced the growth of HCC827GR cells xenograft
tumors in nude mice. Our study provides evidence that ErbB3 might be a client for Hsp90 in Met-amplified NSCLCs. In conclusion, we demonstrate that inhibition of Hsp90 dampens the activation of EGFR- or c-Met-mediated survival of Met-amplified NSCLCs and that
WK88-1 as a Hsp90 inhibitor alleviates
gefitinib resistance in HCC827GR cells.