Korea University Identifies Novel Inhibitor HVH-2930 Showing Promise in Overcoming Trastuzumab Resistance in HER2-Positive Breast Cancer

New C-terminal HSP90 Inhibitor Demonstrates Efficacy Against Drug-Resistant Breast Cancer Cells

SEOUL, South Korea, June 26, 2024 /PRNewswire/ — Korean scientists have investigated HVH-2930, an innovative HSP90 inhibitor in reshaping HER2-positive breast cancer treatment. Unlike previous HSP90 inhibitors, this compound circumvents limitations by bypassing heat shock response induction. It demonstrates promising efficacy in inducing cancer cell apoptosis and effectively overcomes treatment resistance. In preclinical studies, HVH-2930 showed substantial promise, offering hope for better treatment outcomes. Its potential for diverse HER2-overexpressing malignancies indicates a paradigm shift in cancer therapy, anticipating enhanced effectiveness and increased availability.

HER2-positive breast cancer, known for its aggressive nature due to the overexpression of the HER2 protein, poses significant challenges in treatment. Current standard treatments for HER2-positive breast cancer typically involve a combination of HER2-targeted therapies like trastuzumab, chemotherapy, and hormone therapy. However, the emergence of resistance highlights the need for novel approaches for improved outcomes.

In this relentless pursuit of treatment solutions, a team of researchers at Korea University led by Professor Jae Hong Seo have achieved a significant milestone with the development of HVH-2930, a promising inhibitor targeting heat shock protein 90 (HSP90), the findings of which were published in Theranostics on 31 March 2024. Prof. Seo shares, “We have highlighted the pivotal role of HSP90, an oncogenic protein, in fueling tumor growth by activating key receptor tyrosine kinases, including HER2. While previous N-terminal HSP90 inhibitors faced challenges like inducing the heat shock response (HSR) and toxicity, HVH-2930, a C-terminal HSP90 inhibitor, shows promise.”

The study utilized both in vivo and in vitro methods to investigate HER2-positive breast cancer and potential treatments. In laboratory settings, breast cancer cells were cultured alongside normal mammary cells, using advanced cytometry techniques to assess cell viability, apoptosis, and functionality. Additionally, protein interactions were studied to uncover underlying molecular processes. In mouse models, tumor cell implantation was used to study tumor growth dynamics and treatment responses.

The findings revealed that HVH-2930 effectively induced apoptosis in breast cancer cells without triggering the heat shock response (HSR), a notable feature that distinguishes it from other treatments. By selectively targeting HSP90, HVH-2930 downregulated HER2 signaling, crucial in breast cancer progression. Impressively, in xenograft mouse models, HVH-2930 inhibited tumor growth, angiogenesis, and cancer stem cell-like properties without causing toxicity. Moreover, when combined with paclitaxel, HVH-2930 exhibited a synergistic antitumor effect, suggesting its potential as a promising therapeutic strategy for HER2-positive breast cancer.  These results signify a significant advancement in targeting the HSP90 chaperone machinery for breast cancer treatment.

Prof. Seo shares “HVH-2930 stands as a groundbreaking advancement in meeting the critical needs of HER2-positive breast cancer patients, notably those resistant to trastuzumab. With its potential application in other HER2-overexpressing cancers like gastric and esophageal cancers, it holds promise for treating a wider range of patients. Moreover, its anticipated affordability compared to current therapies could significantly enhance accessibility, particularly in resource-limited settings such as underdeveloped countries.”


Title of original paper: The HSP90 inhibitor HVH-2930 exhibits potent efficacy against trastuzumab-resistant HER2-positive breast cancer

Journal: Theranostics

DOI: https://doi.org/10.7150/thno.93236 

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SOURCE Korea University College of Medicine