Related Experiment Video
Updated: Mar 28, 2026
Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
Biomarkers That Predict Sensitivity to Heat Shock Protein 90 Inhibitors
Komal Jhaveri1, Sarat Chandarlapaty1, Neil Iyengar1
1Memorial Sloan Kettering Cancer Center, New York, NY.
Introduction:
Heat shock protein (HSP) 90, a viable target for cancer treatment, mediates the maturation and stabilization of client oncoproteins. HSP90 inhibitors (HSP90i) are potentially active in a variety of tumors, but therapeutic benefit is confirmed in only a small subset. We explored potential biomarkers across multiple studies of HSP90i in advanced solid tumors.
Patients And Methods:
Archived tumor specimens from patients treated with HSP90i in 7 different phase I/II trials at Memorial Sloan Kettering Cancer Center were identified. Tumor tissue was tested using immunohistochemistry; estrogen, progesterone, and androgen receptors ≥ 1% positive and < 1% negative; HSP90 and HSP70: 0, 1 + negative, and 2+, 3 + positive; phosphatase and tensin homolog: 0 negative, 1 reduced, and 2 positive; HER2: 0, 1 + negative, 2 + equivocal, 3 + positive; and epidermal growth factor receptor: 0 negative, and 1+, 2+, 3 + positive. The expression of the biomarker panel was correlated with clinical benefit (CB) (defined by overall response [ORR] or CB by the "8-week" scan) using Fisher exact test.
Results:
Adequate tissue was available for 51 of 158 patients (32%), including 10 different solid tumors. Of these, 71% (36 of 51) and 51% (26 of 51) patients met the criteria to assess CB by best ORR or by the "8-week scan" assessment, respectively. Breast was the most frequent tumor. The mean duration of HSP90i therapy was 55 days (range, 16-411 days). There were 16 responses (4 partial response; 12 stable disease); 13 of 16 responses strongly correlated with HER2-positive status (P = .001).
Conclusion:
Our findings suggest HER2 as a sensitive client and perhaps the only effective biomarker for sensitivity to these HSP90i.
Insights
Heat shock protein 90 inhibitors show promise in cancer treatment, but identifying responsive patients is key. This study found HER2-positive status strongly correlates with clinical benefit from HSP90 inhibitors in advanced solid tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Heat shock protein 90 (HSP90) is crucial for stabilizing oncoproteins in cancer.
- HSP90 inhibitors (HSP90i) have potential anticancer activity but limited confirmed therapeutic benefit.
- Identifying predictive biomarkers for HSP90i is essential for effective cancer treatment.
Purpose of the Study:
- To explore potential biomarkers for predicting response to HSP90 inhibitors in advanced solid tumors.
- To correlate biomarker expression with clinical benefit in patients treated with HSP90i.
- To identify sensitive clients of HSP90 that predict response to HSP90i therapy.
Main Methods:
- Retrospective analysis of tumor specimens from 7 Phase I/II trials of HSP90i.
- Immunohistochemistry was used to assess expression of various biomarkers including hormone receptors, HSP90, HSP70, PTEN, HER2, and EGFR.
- Correlation of biomarker expression with clinical benefit (overall response or 8-week scan assessment) using Fisher exact test.
Main Results:
- Adequate tissue was available for 51 of 158 patients across 10 solid tumor types.
- 16 responses (4 partial response, 12 stable disease) were observed.
- 13 of 16 responses strongly correlated with HER2-positive status (P = .001).
Conclusions:
- HER2 appears to be a sensitive client protein for HSP90 inhibitors.
- HER2-positive status may be a key predictive biomarker for sensitivity to HSP90 inhibitors.
- Further validation is needed, but HER2 status shows promise for guiding HSP90i therapy.
