Mechanisms of Resistance to Hsp90 Inhibitor Drugs: A Complex Mosaic Emerges

Mechanisms of Resistance to Hsp90 Inhibitor Drugs: A Complex Mosaic Emerges

The molecular chaperone Hsp90 holds great promise as a cancer drug target, despite some of the initial clinical trials of Hsp90 inhibitor drugs having not lived up to expectation. Effective use of these drugs will benefit greatly from a much more detailed understanding of the factors that contribute to resistance, whether intrinsic or acquired. We review how cell culture studies have revealed a...

The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms.

PURPOSE The clinical use of BRAF inhibitors is being hampered by the acquisition of drug resistance. This study shows the potential therapeutic use of the HSP90 inhibitor (XL888) in six different models of vemurafenib resistance. EXPERIMENTAL DESIGN The ability of XL888 to inhibit growth and to induce apoptosis and tumor regression of vemurafenib-resistant melanoma cell lines was shown in vit...

A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells.

Pancreatic cancer is an aggressive disease with multiple biochemical and genetic alterations. Thus, a single agent to hit one molecular target may not be sufficient to treat this disease. The purpose of this study is to identify a novel Hsp90 inhibitor to disrupt protein-protein interactions of Hsp90 and its cochaperones for down-regulating many oncogenes simultaneously against pancreatic cance...

Resistance proof, folding-inhibitor drugs

Conventional drugs work, as a rule, by inhibiting the enzymatic activity of specific proteins, capping their active site. In this paper we present a model of non-conventional drug design based on the inhibiting effects small peptides obtained from segments of the protein itself have on the folding ability of the system. Such peptides attach to the newly expressed (unfolded) protein and inhibit ...

Study of resistance to cucumber mosaic virus watermelon mosaic virus and zucchini yellow mosaic virus in melon cultivars