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Updated: Mar 6, 2026
Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
Heat shock protein antagonists in early stage clinical trials for NSCLC
Lizza E L Hendriks1, Anne-Marie C Dingemans1
1a Department of Pulmonary Diseases, GROW - School for oncology and developmental biology , Maastricht University Medical Center+ , Maastricht , The Netherlands.
Introduction:
Cancer cells have a higher need of chaperones than normal cells to prevent the toxic effects of intracellular protein misfolding and aggregation. Heat shock proteins (Hsps) belong to these chaperones; they are classified into families according to molecular size. Hsps are upregulated in many cancers and inhibition can inhibit tumor growth by destabilizing proteins necessary for tumor survival. In non-small cell lung cancer (NSCLC), there are three different Hsp antagonist classes that are in (early) clinical trials: Hsp90, Hsp70 and Hsp27 inhibitors. Areas covered: The rationale to use Hsp inhibitors in NSCLC will be summarized and phase I-III trials will be reviewed. Expert opinion: Several Hsp90 inhibitors have been tested in phase I-III trials, until now none was positive in unselected NSCLC; therefore development of AUY922, ganetespib and retaspimycin was halted. Results seem more promising in molecularly selected patients, especially in ALK-rearranged NSCLC. Hsp27 is overexpressed in squamous NSCLC and is a mechanism of chemotherapy resistance. The Hsp27 inhibitor apatorsen is now tested in squamous NSCLC. No phase II/III data are known for Hsp70 inhibitors. Combination of Hsp inhibitors with heat shock transcription factor 1 inhibitors or focal adhesion kinase inhibitors might be of interest for future trials.
Insights
Heat shock protein (Hsp) inhibitors show promise for non-small cell lung cancer (NSCLC). While Hsp90 inhibitors faced setbacks in unselected NSCLC, they may benefit molecularly selected patients, particularly those with ALK rearrangements.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cancer cells rely on heat shock proteins (Hsps) as chaperones to manage protein misfolding and aggregation.
- Hsps are upregulated in many cancers, and their inhibition can impede tumor growth by destabilizing essential survival proteins.
- In non-small cell lung cancer (NSCLC), inhibitors targeting Hsp90, Hsp70, and Hsp27 are under investigation.
Purpose of the Study:
- To summarize the rationale for employing Hsp inhibitors in NSCLC treatment.
- To review clinical trials (Phase I-III) involving Hsp inhibitors in NSCLC.
Main Methods:
- Review of clinical trial data for Hsp90, Hsp70, and Hsp27 inhibitors in NSCLC.
- Analysis of patient selection strategies, including molecular profiling (e.g., ALK rearrangements).
Main Results:
- Hsp90 inhibitors (AUY922, ganetespib, retaspimycin) have not shown efficacy in unselected NSCLC patients, halting their development.
- Promising results for Hsp90 inhibitors are observed in molecularly selected NSCLC, especially those with ALK rearrangements.
- Hsp27 is overexpressed in squamous NSCLC, contributing to chemotherapy resistance; the Hsp27 inhibitor apatorsen is under evaluation.
Conclusions:
- Hsp inhibitors represent a potential therapeutic strategy for NSCLC, particularly in targeted patient populations.
- Future trials may explore combinations of Hsp inhibitors with other agents, such as heat shock transcription factor 1 or focal adhesion kinase inhibitors.
