한빛사 논문
Jung Min Park1,2†, Yoon-Jae Kim1,2,3†, Soeun Park1,2, Minsu Park1,2, Lee Farrand4, Cong-Truong Nguyen5, Jihyae Ann5, Gibeom Nam6, Hyun-Ju Park6, Jeewoo Lee5*, Ji Young Kim1,3* and Jae Hong Seo1,2,3*
1Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea.
2Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea.
3Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Guro Hospital Campus, 97 Gurodong-gil, Guro-gu, Seoul 08308, Republic of Korea.
4Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia 5000, Australia.
5Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
6School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea.
Jung Min Park and Yoon-Jae Kim contributed equally to this work.
*Corresponding author
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 CD24low/CD44high 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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