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Heat Shock Protein 90 Inhibitors in Lung Cancer Therapy

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Heat Shock Proteins in Signaling Pathways

Part of the book series: Heat Shock Proteins ((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.

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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

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Acknowledgements

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

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA

    Suman Chatterjee & Timothy F. Burns

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  1. Suman Chatterjee
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  2. Timothy F. Burns
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Correspondence to Timothy F. Burns .

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  1. Professor, Department of Medicine and Director, Precision Therapeutics Proteogenomics Diagnostic Center Eleanor N. Dana Cancer Center, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA

    Alexzander A. A. Asea

  2. Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA

    Punit Kaur

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Chatterjee, S., Burns, T.F. (2019). Heat Shock Protein 90 Inhibitors in Lung Cancer Therapy. In: Asea, A., Kaur, P. (eds) Heat Shock Proteins in Signaling Pathways. Heat Shock Proteins, vol 17. Springer, Cham. https://doi.org/10.1007/978-3-030-03952-3_19

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