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Role of HSP90 Inhibitors in the Treatment of Cancer

  • Geraldine O’Sullivan Coyne
  • Cecilia Monge
  • Alice P. ChenEmail author
Chapter
Part of the Heat Shock Proteins book series (HESP, volume 19)

Abstract

The 90-kDa heat shock protein HSP90 is a member of a highly evolutionarily conserved class of molecular chaperone proteins indispensable for the development of cancer; when activated by cellular stress, HSP90 stabilizes oncogenic substrate “client” proteins involved in cellular processes that promote tumorigenesis. HSP90 inhibition attenuates this stabilization of aberrant client proteins in tumor cells, allowing for simultaneous targeting of multiple pathways involved in cancer cell survival. HSP90 inhibitors have been assessed as potential oncologic therapies in several preclinical and clinical studies. Although preclinically promising results have been measured, these results have not translated yet into major clinical efficacy. Combinations of HSP90 inhibitors with approved and investigational oncology drugs may represent further opportunities for the use of these agents in patients with cancer. This chapter reviews some of the important early clinical milestones observed in studies of first- and second-generation HSP90 inhibitors used as single agents and in combination. In the conclusion, possible reasons for the lack of therapeutic benefit in clinical studies are considered.

Keywords

Angiogenesis Heat shock protein 90 HSP90 inhibitor Metastasis Molecular chaperone Oncogenic driver 

Abbreviations

AE

Adverse event

ALK

Anaplastic lymphoma kinase

BRAF

Serine/threonine-protein kinases B-Raf

CDK

Cyclin-dependent kinase

CRAF

Serine/threonine-protein kinases C-Raf

CRC

Colorectal carcinoma

DLT

Dose-limiting toxicity

EGFR

Epidermal growth factor receptor

EMT

Epithelial-to-mesenchymal transition

GDNF

Glial cell line-derived neurotrophic factor

HER2

Human epidermal growth factor receptor 2

HGF

Hepatocyte growth factor

HSP

Heat shock protein

HSP90

Heat shock protein 90

MBC

Metastatic breast cancer

MTD

Maximum tolerated dose

NSCLC

Non-small cell lung cancer

ORR

Overall response rate

TNBC

Triple-negative breast cancer

Notes

Acknowledgements

Special thanks to Sarah Miller, PhD.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Geraldine O’Sullivan Coyne
    • 1
  • Cecilia Monge
    • 1
  • Alice P. Chen
    • 1
    Email author
  1. 1.Division of Cancer Treatment and Diagnosis and Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaUSA

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