In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3712-3712
Abstract:
Purpose: Triple-negative breast cancer (TNBC) still relies on non-selective cytotoxic anticancer agents due to the absence of established molecular targets for the phenotype. The heat shock protein 90 (HSP90) is a promising therapeutic target because it affects the overall progression of cancer, including cell proliferation, angiogenesis and metastasis. A variety of N-terminal HSP90 inhibitors have been tried several times in clinical trials, but none have been approved for clinical use to date due to issues including heat shock response (HSR) induction, undesirable effects, and clinical toxicity. In this study, we sought to investigate whether a novel C-terminal HSP90 inhibitor SL-145 could resolve metastasis in TNBC through inhibition of cancer stem-like properties. Experimental Design: The effects of SL-145 on TNBC cell lines in vitro were evaluated in terms of cell proliferation, apoptosis, caspase-3 activity, breast cancer stem cell (BCSC)-like properties and heat shock response. An orthotopic allograft model with 4T1 mammospheres was used to examine the effect of SL-145 on tumor growth and metastasis in vivo. Results: SL-145 induces apoptosis without triggering the HSR and simultaneously inhibits several oncogenic signaling pathways including AKT, MEK/ERK and JAK2/STAT3. SL-145 effectively targets BCSC-like properties with significant reductions in CD44, CD49f and ALDH1 expression as well as impairment of mammosphere-forming ability. To confirm the physiological relevance of our in vitro observations, we investigated the effects of SL-145 on tumor growth, angiogenesis and metastasis in mammosphere-derived allograft tumors with self-renewal capacity. SL-145 administration reduced tumor burden and angiogenesis, which were enriched in BCSCs, and it resulted in significant reductions in lung and liver metastases. In addition, no toxic effects of inhibitors on markers of liver or renal function were observed. Conclusion: Our findings suggest that SL-145 may represent an effective therapeutic approach for targeting cancer stem cells and simultaneous inhibition of the HSP90 client oncoprotein to treat TNBC with a heterogeneous and aggressive nature. Citation Format: Minsu Park, Tae-Min Cho, Soeun Park, Jung Min Park, Juyeon Seo, Dongmi Ko, Seongjae Kim, So Ra Seuk, Yong Gu Kang, Kee Dal Nam, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo. The C-terminal HSP90 inhibitor, a novel deguelin derivative, exerts anti-metastatic effects in triple-negative breast cancer by targeting cancer stem-like properties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3712.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2022-3712
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2022
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
