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Heat Shock Protein 90 Inhibitors in Lung Cancer Therapy

  • Suman Chatterjee
  • Timothy F. BurnsEmail author
Chapter
Part of the Heat Shock Proteins book series (HESP, volume 17)

Abstract

Heat shock protein 90 (HSP90) plays crucial roles in intracellular quality control mechanisms leading to cytoprotection against variety of stressors including hypoxia, oxidative and thermal and oncogenic stress. The chaperoning activity of the evolutionary conserved and ubiquitously expressed HSP90 is adenosine triphosphate (ATP)–dependent and is essential for the folding, maturation, stabilization, activation or proteolytic degradation of its diverse array of client proteins, many of which are products of driver oncogenes in multiple cancers. Hence, tumorigenesis regulation by HSP90 chaperonage function has been the subject of extensive investigation for decades. Targeted HSP90 inhibition has shown promise and may provide an effective and alternate therapeutic approach to treat patients with lung cancer, especially non-small cell lung cancer (NSCLC) with specific mutational background or that have been characterized to show acquired resistance to other drugs targeting different signaling proteins. Although development of HSP90 inhibitors has spanned decades, both preclinically and clinically, the promise is far from being reached. In this chapter, we discuss the potential of HSP90 inhibition, and the preclinical and clinical development and future of important HSP90 small molecule inhibitors that have been or will be critical for lung cancer therapeutics.

Keywords

17-AAG EGFR Ganetespib HSP90 KRAS Lung cancer NSCLC 

Abbreviations

ADC

adenocarcinoma

ADP

adenosine diphosphate

ATP

adenosine triphosphate

CTD

C-terminal domain

EGFR

epidermal growth factor receptor

ER

endoplasmic reticulum

FDA

US Food Administration

GM

geldanamycin

HSF

heat shock factor

HSP90

heat shock protein 90

HSP

heat shock protein gene

MAPK

mitogen-activated protein kinase

MD

middle domain

NGS

next generation sequencing

NSCLC

non-small cell lung cancer

NTD

N-terminal domain

ORR

objective response rate

OS

overall survival

PFS

progression free survival

RD

radicicol

ROS

reactive oxygen species

SCC

squamous cell carcinoma

TKI

tyrosine kinase inhibitor

TRP

tetratricopeptide repeat

Notes

Acknowledgements

We would like to acknowledge the LUNGevity Foundation for support of preclinical Hsp90 inhibitor studies.

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Medicine, Division of Hematology Oncology, UPMC Hillman Cancer CenterUniversity of PittsburghPittsburghUSA

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