Hsp90, an unlikely ally in the war on cancer

Abstract

On the surface heat shock protein 90 (Hsp90) is an unlikely drug target for the treatment of any disease, let alone cancer. Hsp90 is highly conserved and ubiquitously expressed in all cells. There are two major isoforms α and β encoded by distinct genes and together they may constitute 1%-3% of the cellular protein. Deletion of the protein is embryonic lethal and there are no recognized polymorphisms suggesting an association or causal relationship with any human disease. With respect to cancer, the proteins absence from two recent high profile articles, 'Hallmarks of cancer: the next generation' [Hanahan & Weinberg (2011) Cell 144, 646-674] and 'Comprehensive molecular portraits of human breast tumours' [Koboldt et al. (2012) Nature] underlines the perception that it is an unlikely bona fide target to treat this disease. Yet, to date, there are 17 distinct Hsp90 inhibitors in clinical trials for multiple indications in cancer. The protein has been championed for over 20 years by the National Cancer Institute (Bethesda, MD, USA) as a cancer target since the discovery of the antitumor activity of the natural product geldanamycin. This review aims to look at the conundrum of why Hsp90 can even be considered a druggable target for the treatment of cancer. We propose that in contrast to the majority of chemotherapeutics our growing armamentarium of investigational Hsp90 drugs represents an elegant choice that offers real hope in the long-term treatment of certain cancers.

Fig. 1

Hsp90 differences between tumor cells and adjacent normal cells. Hsp90 is elevated in tumor cells, induction. Hsp90 is activated (red) in tumor cells and localizes to the cell surface, whereas in normal cells Hsp90 resides exclusively in the cytosol.

Fig. 2

Labeled Hsp90 in various lysed mouse tissues normalized to total protein. The fluorescently labeled small molecule inhibitor HS-27 detects active Hsp90, and surprisingly two xenograft tumor samples did not exhibit the highest active Hsp90 to total protein ratio.

Fig. 3

Directed chemical evolution of a selective affinity medium for Hsp90. SDS/PAGE silver stain showing the effects of different side chain modifications on Hsp90 recovery and recovery of nonspecifically bound proteins. Selectivity towards Hsp90 was demonstrated by inclusion of 1 mM of the free ligand (+) in the tissue extract prior to mixing with affinity resin. Mass spectrometry was used to define all of the bound protein. In the azo-6-PEG resin bound proteins were eluted with 25 mM sodium dithionite in NaCl/P_i. PEG, polyethylene glycol. Figure reproduced from [47].

Fig. 4

In vivo pharmacology of SNX-5422. Effects on BT-474 tumor-bearing nude mice (n = 10) dosed with vehicle or (1) 10 mg·kg⁻¹ SNX-5422 (SNX) by mouth three times per week, (2) trastuzumab (TZB) 3 mg·kg⁻¹ intravenously twice per week, (3) 10 mg·kg⁻¹ SNX by mouth three times per week and TZB 3 mg·kg⁻¹ intravenously twice per week or (4) 40 mg·kg⁻¹ SNX three times per week. Dosing in all drug-treated groups was for only the first 3 weeks. All groups were followed for 6 months or until sacrifice due to tumor burden. Figure reproduced from [41].