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Although epidermal growth factor receptor‐tyrosine kinase inhibitors ( EGFR ‐ TKI s) 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 ‐ TKI s. 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  WK 88‐1 in Met‐amplified‐ and gefitinib‐resistant ( HCC 827 GR )  NSCLC  cells and its parental  HCC 827 cells. Treatment with  WK 88‐1 reduced the cell viability in both  HCC 827 and  HCC 827 GR  cells, which was associated with marked decrease in the constitutive expression of Hsp90 client proteins, such as  EGFR , ErbB2, ErbB3, Met and Akt. Moreover,  WK 88‐1 attenuated phosphorylation of these Hsp90 client proteins and reduced the anchorage‐independent growth of  HCC 827 GR  cells. Administration of  WK 88‐1 did not cause hepatotoxicity in animals and significantly reduced the growth of  HCC 827 GR  cells xenograft tumors in nude mice. Our study provides evidence that ErbB3 might be a client for Hsp90 in Met‐amplified  NSCLC s. In conclusion, we demonstrate that inhibition of Hsp90 dampens the activation of  EGFR ‐ or c‐Met‐mediated survival of Met‐amplified  NSCLC s and that  WK 88‐1 as a Hsp90 inhibitor alleviates gefitinib resistance in  HCC 827 GR  cells.

Anti‐tumor activity of WK 88‐1, a novel geldanamycin derivative, in gefitinib‐resistant non‐small cell lung cancers with Met amplification