The HSP90 inhibitor HVH-2930 exhibits potent efficacy against trastuzumab-resistant HER2-positive breast cancer.

Abstract

Rationale: Resistance to targeted therapies like trastuzumab remains a critical challenge for HER2-positive breast cancer patients. Despite the progress of several N-terminal HSP90 inhibitors in clinical trials, none have achieved approval for clinical use, primarily due to issues such as induction of the heat shock response (HSR), off-target effects, and unfavorable toxicity profiles. We sought to examine the effects of HVH-2930, a novel C-terminal HSP90 inhibitor, in overcoming trastuzumab resistance. Methods: The effect of HVH-2930 on trastuzumab-sensitive and -resistant cell lines in vitro was evaluated in terms of cell viability, expression of HSP90 client proteins, and impact on cancer stem cells. An in vivo model with trastuzumab-resistant JIMT-1 cells was used to examine the efficacy and toxicity of HVH-2930. Results: HVH-2930 was rationally designed to fit into the ATP-binding pocket interface cavity of the hHSP90 homodimer in the C-terminal domain of HSP90, stabilizing its open conformation and hindering ATP binding. HVH-2930 induces apoptosis without inducing the HSR but by specifically suppressing the HER2 signaling pathway. This occurs with the downregulation of HER2/p95HER2 and disruption of HER2 family member heterodimerization. Attenuation of cancer stem cell (CSC)-like properties was associated with the downregulation of stemness factors such as ALDH1, CD44, Nanog and Oct4. Furthermore, HVH-2930 administration inhibited angiogenesis and tumor growth in trastuzumab-resistant xenograft mice. A synergistic effect was observed when combining HVH-2930 and paclitaxel in JIMT-1 xenografts. Conclusion: Our findings highlight the potent efficacy of HVH-2930 in overcoming trastuzumab resistance in HER2-positive breast cancer. Further investigation is warranted to fully establish its therapeutic potential.

• Authors: Minsu Park, Eunsun Jung, Jung Min Park, Soeun Park, Dongmi Ko, Juyeon Seo, Seongjae Kim, Kee Dal Nam, Yong Koo Kang, Lee Farrand, Van-Hai Hoang, Cong-Truong Nguyen, Minh Thanh La, Gibeom Nam, Hyun-Ju Park, Jihyae Ann, Jeewoo Lee, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo
• Journal: Theranostics (Theranostics) Vol. 14 Issue 6 Pg. 2442-2463 ( 2024) ISSN: 1838-7640 [Electronic] Australia
• PMID: 38646654 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• HSP90 Heat-Shock Proteins
• Trastuzumab
• Receptor, ErbB-2
• ERBB2 protein, human
• Antineoplastic Agents

Topics

• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Drug Resistance, Neoplasm (drug effects)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Trastuzumab (pharmacology, therapeutic use)
• Animals
• Female
• Receptor, ErbB-2 (metabolism, antagonists & inhibitors)
• Cell Line, Tumor
• Mice
• Xenograft Model Antitumor Assays
• Neoplastic Stem Cells (drug effects, metabolism)
• Mice, Nude
• Apoptosis (drug effects)
• Cell Survival (drug effects)
• Antineoplastic Agents (pharmacology)