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Updated: May 21, 2026
Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
Molecular pathways: targeting hsp90--who benefits and who does not
Maurizio Scaltriti1, Shaheenah Dawood, Javier Cortes
1Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA. mscaltriti@partners.org
Abstract:
Many kinases and hormone receptors, important for cancer cell proliferation and survival, bind to and are dependent on the Hsp90 cycle for their folding and maturation. This provides the rationale for the development of small-molecule ATP competitors that, inhibiting Hsp90 function, lead to degradation of the "client" proteins. After continual efforts to improve the pharmacologic properties and the tolerability of these molecules, several Hsp90 inhibitors have exhibited activity in both preclinical models and in the clinical setting. As is the case with many other targeted agents, patient selection seems to be the major limitation to the success of these compounds. ERBB2-positive patients with breast cancer are exquisitely sensitive to Hsp90 inhibition. This is because ERBB2 is indispensable for growth and survival of this subtype of cancer, and at the same time ERBB2 is a client protein strictly dependent on Hsp90 for its maturation and stability. Extensive preclinical work identifying other ERBB-like client proteins will likely lead to the ability to enhance selection of appropriate patients for enrollment in more rational clinical trials. Hsp90 inhibition has also been reported to synergize with other therapeutic agents. Several ongoing studies testing different combinations of Hsp90 inhibitors with other targeted agents will confirm whether Hsp90 inhibition can potentiate the efficacy of targeted therapy and/or prevent the emergence of drug resistance.
Insights
Heat shock protein 90 (Hsp90) inhibitors show promise in cancer therapy by degrading client proteins essential for tumor growth. Patient selection, particularly for ERBB2-positive breast cancer, is key to maximizing Hsp90 inhibitor efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Heat shock protein 90 (Hsp90) is crucial for the folding and maturation of numerous kinases and hormone receptors involved in cancer cell proliferation and survival.
- Small-molecule ATP competitors targeting Hsp90 aim to inhibit its function, leading to the degradation of these essential "client" proteins.
Purpose of the Study:
- To explore the therapeutic potential of Hsp90 inhibitors in cancer treatment.
- To investigate the role of patient selection in optimizing Hsp90 inhibitor efficacy.
- To identify potential synergistic effects of Hsp90 inhibition with other therapeutic agents.
Main Methods:
- Development and evaluation of small-molecule Hsp90 inhibitors.
- Preclinical studies in cancer models.
- Clinical trials assessing Hsp90 inhibitor activity and tolerability.
- Identification of Hsp90 client proteins, such as ERBB2.
Main Results:
- Several Hsp90 inhibitors have demonstrated activity in preclinical and clinical settings.
- ERBB2-positive breast cancer patients show particular sensitivity to Hsp90 inhibition due to ERBB2's dependence on Hsp90.
- Hsp90 inhibition has shown potential for synergistic effects with other therapeutic agents.
Conclusions:
- Hsp90 inhibitors represent a promising targeted therapy approach for various cancers.
- Refining patient selection strategies, particularly for ERBB2-positive cancers, is critical for successful Hsp90 inhibitor treatment.
- Further research into Hsp90 inhibitor combinations may enhance efficacy and overcome drug resistance.
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