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 Journal Article
| Authors: | Bachleitner-Hofmann, T.; Sun, M. Y.; Chen, C. T.; Liska, D.; Zeng, Z.; Viale, A.; Olshen, A. B.; Mittlboeck, M.; Christensen, J. G.; Rosen, N.; Solit, D. B.; Weiser, M. R. |
| Article Title: | 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 |
| Abstract: | Purpose: Heat shock protein-90 (HSP-90), a molecular chaperone required by numerous oncogenic kinases [e.g., HER-2, epidermal growth factor receptor (EGFR), Raf-1, v-Src, and 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 that is constitutively active in tumor cells with MET oncogene amplification, has recently been identified as another HSP-90 client. Experimental Design: The 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. Results: 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 that have acquired resistance to MET kinase inhibition. Conclusions: Our study provides evidence for the efficacy of HSP-90 inhibition in MET-amplified cancer cells, particularly when MET kinase inhibitor resistance has emerged. © 2011 AACR. |
| Keywords: | protein kinase b; controlled study; unclassified drug; human cell; drug dose comparison; drug dose reduction; drug efficacy; nonhuman; mouse; animal tissue; apoptosis; gene amplification; protein degradation; epidermal growth factor receptor; epidermal growth factor receptor 2; animal experiment; animal model; antineoplastic activity; cancer cell culture; tumor xenograft; protein tyrosine kinase; cancer therapy; oncogene; nude mouse; cancer cell; tumor cell line; heat shock protein 90 inhibitor; cell cycle arrest; drug bioavailability; tumor; drug dose increase; prodrug; snx 2112; tyrosine kinase met |
| Journal Title: | Clinical Cancer Research |
| Volume: | 17 |
| Issue: | 1 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2011-01-01 |
| Start Page: | 122 |
| End Page: | 133 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-10-0253 |
| PROVIDER: | scopus |
| PUBMED: | 21208906 |
| PMCID: | PMC3263825 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 March 2011" - "CODEN: CCREF" - "Source: Scopus" |
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