Generic placeholder image

Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Tumor-Intrinsic and Tumor-Extrinsic Factors Impacting Hsp90- Targeted Therapy

Author(s): S.V. Alarcon, M. Mollapour, M.-J. Lee, S. Tsutsumi, S. Lee, Y.S. Kim, T. Prince, A.B. Apolo, G. Giaccone, W. Xu, L.M. Neckers and J.B. Trepel

Volume 12, Issue 9, 2012

Page: [1125 - 1141] Pages: 17

DOI: 10.2174/156652412803306729

Price: $65

conference banner
Abstract

In 1994 the first heat shock protein 90 (Hsp90) inhibitor was identified and Hsp90 was reported to be a target for anticancer therapeutics. In the past 18 years there have been 17 distinct Hsp90 inhibitors entered into clinical trial, and the small molecule Hsp90 inhibitors have been highly valuable as probes of the role of Hsp90 and its client proteins in cancer. Although no Hsp90 inhibitor has achieved regulatory approval, recently there has been significant progress in Hsp90 inhibitor clinical development, and in the past year RECIST responses have been documented in HER2-positive breast cancer and EML4-ALK-positive non-small cell lung cancer. All of the clinical Hsp90 inhibitors studied to date are specific in their target, i.e. they bind exclusively to Hsp90 and two related heat shock proteins. However, Hsp90 inhibitors are markedly pleiotropic, causing degradation of over 200 client proteins and impacting critical multiprotein complexes. Furthermore, it has only recently been appreciated that Hsp90 inhibitors can, paradoxically, cause transient activation of the protein kinase clients they are chaperoning, resulting in initiation of signal transduction and significant physiological events in both tumor and tumor microenvironment. An additional area of recent progress in Hsp90 research is in studies of the posttranslational modifications of Hsp90 itself and Hsp90 co-chaperone proteins. Together, a picture is emerging in which the impact of Hsp90 inhibitors is shaped by the tumor intracellular and extracellular milieu, and in which Hsp90 inhibitors impact tumor and host on a microenvironmental and systems level. Here we review the tumor intrinsic and extrinsic factors that impact the efficacy of small molecules engaging the Hsp90 chaperone machine.

Keywords: Heat shock protein 90, host, phosphorylation, posttranslational, reactive oxygen species, stroma, systems, anticancer therapeutics, Hsp90 inhibitor, mutations, trastuzumab, proteasome inhibitor, bortezomib, multiple myeloma, proteotoxic stress


Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy