Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors

Abstract

The last decade has seen the molecular chaperone heat shock protein 90 (HSP90) emerge as an exciting target for cancer therapy. This is because HSP90 is involved in maintaining the conformation, stability, activity and cellular localisation of several key oncogenic client proteins. These include, amongst others, ERBB2, C-RAF, CDK4, AKT/PKB, steroid hormone receptors, mutant p53, HIF-1a, survivin and telomerase hTERT. Therefore, modulation of this single drug target offers the prospect of simultaneously inhibiting all the multiple signalling pathways and biological processes that have been implicated in the development of the malignant phenotype. The chaperone function of HSP90 requires the formation of a multichaperone complex, which is dependent on the hydrolysis of ATP and ADP/ATP exchange. Most current inhibitors of HSP90 act as nucleotide mimetics, which block the intrinsic ATPase activity of this molecular chaperone. The first-in-class inhibitor to enter and complete phase I clinical trials was the geldanamycin analogue, 17-allylamino-17-demethoxygeldanamycin. The results of these trials have demonstrated that HSP90 is a valid drug target. Evidence of clinical activity has been seen in patients with melanoma, breast and prostate cancer. This article provides a personal perspective of the present efforts to increase our understanding of the molecular and cellular consequences of HSP90 inhibition, with examples from work in our own laboratory. We also review the discovery and development of novel small-molecule inhibitors and discuss alternative approaches to inhibit HSP90 activity, both of which offer exciting prospects for the future.Endocrine-Related Cancer (2006) 13 S125-S135

Telomerase inhibitor GRN163L inhibits myeloma cell growth in vitro and in vivo

“…Additionally, Hsp90 is a molecular chaperone, required for the attainment of specific conformation, stability and proper functioning of a variety of cellular proteins including telomerase 33 as well as several other proteins implicated in DNA damage repair and telomere maintenance through alternate pathways. 34,35 The rationale for combining Hsp90 inhibitor with GRN163L was to first initiate the destruction of telomeric DNA in cancer cells by treating with a specific inhibitor (GRN163L) and then expedite the degradation of vulnerable telomeres by giving a brief exposure to an agent, which may significantly expedite the destruction of already eroding telomeres through different mechanisms. We chose Hsp90 inhibitor as potentially it could Figure 6 Effect Hsp90 inhibitor 17AAG on GRN163L-induced MM cell death.…”

“…[29][30][31][32][33][34][35] Approximately 8 weeks following bone implantation, 5 Â 10 6 human IL-6-dependent INA6 cells were injected directly into human bone in SCID-hu host. Production of human paraprotein in mouse serum was monitored as an indicator of myeloma cell growth.…”

RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation

“…The induced Hsps play roles as cellular chaperones, and many modulate apoptotic pathways, particularly those involving mitochondria, conferring protection from stressful stimuli including chemotherapeutic agents [15]. Hsp90 client proteins include mutated p53, Bcr-Abl, Raf-1, Akt, HER2 (ErbB2) and hypoxia inducible factor-1alpha (HIF-1alpha) [16].…”

Protein disulfide isomerases are antibody targets during immune-mediated tumor destruction

“…34,35 A third set of antigens consists of heat-responsive protein 12 (HRP12), autophagyrelated 3 (atg3), and autophagy-related 12 (atg12), which enhance the resistance of tumor cells to various forms of stress. 36,37 A fourth group of targets participates in intermediary metabolism and includes farnesyl diphosphate synthetase (FDPS), a key enzyme in the mevalonate biosynthetic pathway that generates cholesterol and isoprenoids, and ATP synthase mitochondrial F1 complex ␦ subunit (atp5d), an important component of oxidative phosphorylation. 38,39 A final set of antigens encompasses nuclear proteins that contribute to chromatin, DNA repair, and transcriptional control.…”