Antitumor activity of SNX-2112, a synthetic heat shock protein-90 inhibitor, in MET-amplified tumor cells with or without resistance to selective MET Inhibition.
Antitumor activity of SNX-2112, a synthetic heat shock protein-90 inhibitor, in MET-amplified tumor cells with or without resistance to selective MET Inhibition.
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DOI：
10.1158/1078-0432.ccr-10-0253
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发表时间：
2011-01-01
期刊：
影响因子：
--
通讯作者：
Weiser MR
中科院分区：
文献类型：
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作者：
Bachleitner-Hofmann T;Sun MY;Chen CT;Liska D;Zeng Z;Viale A;Olshen AB;Mittlboeck M;Christensen JG;Rosen N;Solit DB;Weiser MR
Heat shock protein-90 (HSP-90), a molecular chaperone required by numerous oncogenic kinases (e.g. HER-2, EGFR, Raf-1, v-Src, AKT) for conformational stability, has attracted wide interest as a novel target for cancer therapy. HSP-90 inhibition induces degradation of HSP-90 client proteins, leading to a combinatorial inhibition of multiple oncogenic signaling pathways with consecutive growth arrest and apoptosis. MET, a tyrosine kinase which is constitutively active in tumor cells with MET oncogene amplification, has recently been identified as another HSP-90 client. Aim of our study was to assess the efficacy of SNX-2112, a synthetic HSP-90 inhibitor, in 3 different MET-amplified tumor cell lines (GTL-16, MKN-45 and EBC-1) as well as PR-GTL-16 cells, a GTL-16 subline selected for resistance to the highly selective MET kinase inhibitor PHA-665752. In all cell lines, SNX-2112 led to degradation of MET, HER-2, EGFR and AKT as well as abrogation of Ras/Raf/MEK/MAPK and PI3K/AKT signaling, followed by complete cell cycle arrest. SNX-5542, an orally bioavailable prodrug of SNX-2112, displayed significant antitumor efficacy in vivo in nude mice bearing MET-amplified tumor xenografts. Importantly, HSP-90 inhibition maintained its antitumor efficacy in PR-GTL-16 cells both in vitro and in vivo, suggesting that HSP-90 inhibition could be a particularly valuable strategy in MET-amplified tumors which have acquired resistance to MET kinase inhibition. Our study provides evidence for the efficacy of HSP-90 inhibition in MET-amplified cancer cells, particularly when MET kinase inhibitor resistance has emerged.
