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Review
. 2012 Apr 15;83(8):995-1004.
doi: 10.1016/j.bcp.2011.11.011. Epub 2011 Nov 22.

Hsp90 inhibitors and drug resistance in cancer: the potential benefits of combination therapies of Hsp90 inhibitors and other anti-cancer drugs (V体育安卓版)

Xiangyi Lu  1 , Li Xiao, Luan Wang, Douglas M Ruden
Affiliations
Review

V体育官网入口 - Hsp90 inhibitors and drug resistance in cancer: the potential benefits of combination therapies of Hsp90 inhibitors and other anti-cancer drugs

Xiangyi Lu et al. Biochem Pharmacol. .

Abstract

Hsp90 is a chaperone protein that interacts with client proteins that are known to be in the cell cycle, signaling and chromatin-remodeling pathways. Hsp90 inhibitors act additively or synergistically with many other drugs in the treatment of both solid tumors and leukemias in murine tumor models and humans VSports手机版. Hsp90 inhibitors potentiate the actions of anti-cancer drugs that target Hsp90 client proteins, including trastuzumab (Herceptin™) which targets Her2/Erb2B, as Hsp90 inhibition elicits the drug effects in cancer cell lines that are otherwise resistant to the drug. A phase II study of the Hsp90 inhibitor 17-AAG and trastuzumab showed that this combination therapy has anticancer activity in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. In this review, we discuss the results of Hsp90 inhibitors in combination with trastuzumab and other cancer drugs. We also discuss recent results from yeast focused on the genetics of drug resistance when Hsp90 is inhibited and the implications that this might have in understanding the effects of genetic variation in treating cancer in humans. .

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Figures

Figure 1
Figure 1. Hsp90 and drug resistance in yeast
A, RM11-1a yeast are resistant to rapamycin in the absence of Hsp90. We propose that both BY4716 and RM11-1a Nfs1 proteins are clients for Hsp90 which helps it maintain a rapamycin sensitive phenotype (hexagon), but Nfs1 protein forms a rapamycin-resistant structure (circle) in the absence of Hsp90. B, BY4716 yeast are sensitive to hydroxyurea in the presence of Hsp90. We propose that the BY4716 Mec1 protein is a client for Hsp90 and it forms a structure that confers hydroxyurea sensitivity (hexagon), but the RM11-1a Mec1 protein is not a client for Hsp90 and forms a structure that confers resistance to hydroxyurea (circle). In the absence of Hsp90, we propose that the BY4716 Mec1 protein folds into a structure that confers resistance to hydroxyurea (circle). C, RM11-1a yeast are resistant to oxidative stress (CDNB) in the absence of Hsp90. The BY4716 and RM11-1a NDI1 genes have a SNP in the 3’UTR that affects binding to a hypothetical 3’UTR binding protein in the absence of Hsp90 (circle), but not in the presence of Hsp90 (hexagon). See text for more details. (see [69]).
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