Heat Shock Protein 90 Inhibitors in Lung Cancer Therapy

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.