Abstract #1853: Cancer cells harboring MET gene amplification are sensitive to Hsp90 inhibitor 17-AAG

The proto-oncogene product c-Met is the receptor for hepatocyte growth factor/scatter factor (HGF/SF). MET gene amplification and activating mutations are found to exist in a range of primary human cancers. Deregulation of c-Met is suggested to impact tumor invasion and metastasis. Tumor cells with MET gene amplification are initially sensitive to c-Met tyrosine kinase inhibitors (TKI). Hsp90 is a molecular chaperone that assists the folding, stability and function of a wide variety of cellular proteins, many of which are involved in tumorigenesis. Geldanamycin and its derivative 17-AAG, which is currently undergoing extensive clinical trial, inhibit Hsp90 activity and decrease the protein level of its clients, including c-Met. Therefore, Hsp90 inhibitors are expected to inhibit tumors driven by MET amplification. Here, we evaluated the inhibitory effects of 17-AAG in comparison with the c-Met TKI SU11274 on two cell lines (H1993 and MKN45) harboring MET gene amplification. 17-AAG dramatically decreased c-Met protein level and its autophosphorylation. Activity and/or steady state level of signaling proteins downstream of c-Met, including AKT, ERK and STAT3 are also decreased following 17-AAG. In both cell lines, signaling pathways downstream of c-Met became re-activated a short time after cells were treated with SU11274, despite sustained inhibition of c-Met, suggesting development of resistance to c-Met TKI. In both cell lines, resistance was mediated by PKC \#948;-dependent upregulation of EGFR family members. In striking contrast, 17-AAG reduced PKC \#948; activity and induced sustained inhibition of c-Met signaling. Moreover, 17-AAG inhibited cell growth significantly and induced substantial apoptosis in both cell lines, whereas SU11274 was less effective. Our data demonstrate that Hsp90 inhibition is a promising approach to durably inhibit growth of tumor cells driven by MET gene amplification.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1853.