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Updated: Sep 24, 2025
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
A novel HSP90 inhibitor SL-145 suppresses metastatic triple-negative breast cancer without triggering the heat shock
Ji Young Kim1,2, Tae-Min Cho1,2,3, Jung Min Park1,3
1Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
Abstract:
Despite recent advances, there remains a significant unmet need for the development of new targeted therapies for triple-negative breast cancer (TNBC). Although the heat shock protein HSP90 is a promising target, previous inhibitors have had issues during development including undesirable induction of the heat shock response (HSR) and off-target effects leading to toxicity. SL-145 is a novel, rationally-designed C-terminal HSP90 inhibitor that induces apoptosis in TNBC cells via the suppression of oncogenic AKT, MEK/ERK, and JAK2/STAT3 signaling and does not trigger the HSR, in contrast to other inhibitors. In an orthotopic allograft model incorporating breast cancer stem cell-enriched TNBC tumors, SL-145 potently suppressed tumor growth, angiogenesis, and metastases concomitant with dysregulation of the JAK2/STAT3 signaling pathway. Our findings highlight the potential of SL-145 in suppressing metastatic TNBC independent of the HSR.
Insights
A novel heat shock protein 90 (HSP90) inhibitor, SL-145, shows promise for treating triple-negative breast cancer (TNBC). It effectively suppresses tumor growth and metastasis without inducing the heat shock response (HSR).
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Triple-negative breast cancer (TNBC) lacks effective targeted therapies, presenting a significant unmet clinical need.
- Heat shock protein 90 (HSP90) is a validated therapeutic target, but prior inhibitors faced development challenges due to toxicity and induction of the heat shock response (HSR).
Purpose of the Study:
- To evaluate SL-145, a novel C-terminal HSP90 inhibitor, as a potential targeted therapy for TNBC.
- To assess SL-145's efficacy in preclinical models and determine its mechanism of action, including its effect on the HSR.
Main Methods:
- In vitro studies assessed SL-145's effects on TNBC cell apoptosis and signaling pathways (AKT, MEK/ERK, JAK2/STAT3).
- In vivo efficacy was evaluated using an orthotopic allograft model of TNBC enriched with cancer stem cells.
- Tumor growth, angiogenesis, and metastasis were assessed, alongside HSR induction and JAK2/STAT3 pathway modulation.
Main Results:
- SL-145 induced apoptosis in TNBC cells by suppressing key oncogenic signaling pathways.
- Unlike other inhibitors, SL-145 did not trigger the heat shock response (HSR).
- In vivo, SL-145 significantly suppressed tumor growth, angiogenesis, and metastasis, with notable dysregulation of the JAK2/STAT3 pathway.
Conclusions:
- SL-145 is a novel HSP90 inhibitor with potent anti-tumor and anti-metastatic activity in TNBC models.
- Its ability to suppress tumor progression independently of the HSR offers a potential advantage over existing HSP90 inhibitors.
- SL-145 represents a promising therapeutic candidate for treating metastatic TNBC.
