Abstract 4911: A novel C-terminal of HSP90 inhibitor NCT-547 eliminates cancer stem-like subpopulation in triple-negative breast cancer

Triple-negative breast cancer (TNBC) harbors a higher cancer stem cell (CSC)-like population and exhibits a more aggressive metastatic phenotype. Due to the limitations of currently available targeted therapies, there remains a significant unmet need for the development of new targeted therapies for TNBC. Molecular chaperone heat shock protein 90 (HSP90) is attracting attention as an ideal therapeutic target due to it regulates essential biological functions such as cell proliferation, angiogenesis and metastasis. Although N-terminal HSP90 inhibitors have had little clinical success to date, C-terminal HSP90 inhibitors have received relatively little attention. We sought to investigate the effects of a new rationally designed NCT-547 on apoptosis, breast cancer stem cell (BCSC)-like properties, migration ability and heat shock response (HSR) in vitro and tumor growth and metastasis in CSC-enriched allograft model in vivo. NCT-547 inhibits TNBC cell proliferation by simultaneously inactivating several survival factors including AKT, MEK, and STAT3. In addition, NCT-547 effectively targets BCSC-like properties with impairment of ALDH1 activity, CD44+/CD24- phenotype, and 3D mammosphere-forming ability. The expression of HSF-1 target genes such as Hsp90, Hsp70, Hsp27, Hsp40 and Hsp65 is highly overexpressed in TNBC patients. The mRNA abundances of target genes were significantly decreased after NCT-547 challenge. NCT-547 effectively targets both the proliferating TNBC tumor cells and CSCs, markedly reducing tumor growth, coinciding with decreased Ki-67 proliferation index and enhanced apoptosis. Anti-tumor effect of NCT-457 was independent of heat shock response as evidenced by significant downregulation of HSF1 phosphorylation and expression of downstream targets HSPs members. It is noteworthy that NCT-547 did not affect markers of hepatic and renal acute toxicity and was not cytotoxic in non-malignant cells. NCT-547 may therefore have potential to address current limitations in the treatment of TNBC. Citation Format: Eunsun Jung, Seojin Jang, Daeil Sung, Soeun Park, Minsu Park, Dongmi Ko, Seongjae Kim, Juyeon Seo, Kee Dal Nam, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo, Yong koo Kang, So Ra Seock, Jung Min Park. A novel C-terminal of HSP90 inhibitor NCT-547 eliminates cancer stem-like subpopulation in triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4911.