A novel HSP90 inhibitor targeting the C-terminal domain attenuates trastuzumab resistance in HER2-positive breast cancer
- Authors
- Park, Jung Min; Kim, Yoon-Jae; Park, Soeun; Park, Minsu; Farrand, Lee; Nguyen, Cong-Truong; Ann, Jihyae; Nam, Gibeom; Park, Hyun-Ju; Lee, Jeewoo; Kim, Ji Young; Seo, Jae Hong
- Issue Date
- 20-12월-2020
- Publisher
- BMC
- Keywords
- C-terminal HSP90 inhibitor; NCT-547; HER2-positive breast cancer; Cancer stem cells; Trastuzumab resistance; p95HER2; HER2
- Citation
- MOLECULAR CANCER, v.19, no.1
- Indexed
- SCIE
SCOPUS
- Journal Title
- MOLECULAR CANCER
- Volume
- 19
- Number
- 1
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/50783
- DOI
- 10.1186/s12943-020-01283-6
- ISSN
- 1476-4598
- Abstract
- Trastuzumab resistance in HER2-positive breast cancer is associated with a poorer prognosis. HSP90 is thought to play a major role in such resistance, but N-terminal inhibitors of this target have had little success. We sought to investigate the utility of NCT-547, a novel, rationally-designed C-terminal HSP90 inhibitor in the context of overcoming trastuzumab resistance. NCT-547 treatment significantly induced apoptosis without triggering the heat shock response (HSR), accompanied by caspase-3/- 7 activation in both trastuzumab-sensitive and -resistant cells. NCT-547 effectively promoted the degradation of full-length HER2 and truncated p95HER2, while also attenuating hetero-dimerization of HER2 family members. The impairment of cancer stem-like traits was observed with reductions in ALDH1 activity, the CD24(low)/CD44(high) subpopulation, and mammosphere formation in vitro and in vivo. NCT-547 was an effective inhibitor of tumor growth and angiogenesis, and no toxic outcomes were found in initial hepatic and renal analysis. Our findings suggest that NCT-547 may have applications in addressing trastuzumab resistance in HER2-positive breast cancer.
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Collections - Graduate School > Department of Biomedical Sciences > 1. Journal Articles
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