Extracellular heat shock protein 90 alpha (eHsp90α)'s role in cancer progression and the development of therapeutic strategies

• Published in: European journal of medicinal chemistry Vol. 277; p. 116736
• Main Authors: Reynolds, Tyelor S., Blagg, Brian S.J.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05.11.2024
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer biomarker; Cancer target; Disease Progression; Drug discovery; Extracellular heat shock protein 90 alpha; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Humans; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Small molecule inhibitors; Cancer biomarker; Cancer target; Extracellular heat shock protein 90 alpha; Small molecule inhibitors; Drug discovery
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116736

Heat shock protein 90 alpha (Hsp90α) is an abundantly expressed and evolutionarily conserved molecular chaperone. Hsp90α is the inducible Hsp90 isoform, and its expression and secretion extracellularly (eHsp90α) can be triggered in response to a variety of cellular stresses to protect/activate client proteins and to facilitate cellular adjustment to the stress. As a result, cancers often have high expression levels of intracellular and extracellular (plasma) Hsp90α, allowing them to support their oncogenesis and progression. In fact, (e)Hsp90α has been implicated in regulating processes such as cell signaling transduction, DNA repair, promotion of the Epithelial-to-Mesenchymal Transition (EMT), promotion of angiogenesis, immune response, and cell migration. Hsp90α levels have been correlated with cancer progression and severity in several cancers, indicating that it may be a useful biomarker or drug-target for cancer. To date, the development of intracellular Hsp90α-targeted therapies include standard N-terminal ATP-competitive inhibitors and allosteric regulators that bind to Hsp90α′s middle or C-terminal domain. On-target toxicities and dosing complications as a result of Hsp90α inhibition has driven the development of eHsp90α-targeted therapies. Examples include anti-Hsp90α monoclonal antibodies and cell-impermeable Hsp90α small molecule inhibitors. This review aims to discuss the many roles Hsp90α plays in cancer progression with a focus on the current development of Hsp90α-targeted therapies. A high-resolution pdf of the graphical abstract has been submitted separately for re-scaling. [Display omitted] •Extracellular heat shock protein 90 alpha implicated as a pan-cancer biomarker.•Therapeutics targeting Hsp90α have been developed with various mechanisms of action.•Extracellular Hsp90α as a target for the treatment of cancer.•Extracellular Hsp90α promotes cancer progression and metastasis.