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C 端热休克蛋白 90 抑制剂 NCT-58 可杀死曲妥珠单抗耐药的乳腺癌干细胞样细胞。

The C-terminal HSP90 inhibitor NCT-58 kills trastuzumab-resistant breast cancer stem-like cells.

作者信息

Park Soeun, Kim Yoon-Jae, Park Jung Min, Park Minsu, Nam Kee Dal, Farrand Lee, Nguyen Cong-Truong, La Minh Thanh, Ann Jihyae, Lee Jeewoo, Kim Ji Young, Seo Jae Hong

机构信息

Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea.

Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea.

出版信息

Cell Death Discov. 2021 Nov 13;7(1):354. doi: 10.1038/s41420-021-00743-2.

DOI:10.1038/s41420-021-00743-2
PMID:34775489
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8590693/
Abstract

N-terminal HSP90 inhibitors in development have had issues arising from heat shock response (HSR) induction and off-target effects. We sought to investigate the capacity of NCT-58, a rationally-synthesized C-terminal HSP90 inhibitor, to kill trastuzumab-resistant HER2-positive breast cancer stem-like cells. NCT-58 does not induce the HSR due to its targeting of the C-terminal region and elicits anti-tumor activity via the simultaneous downregulation of HER family members as well as inhibition of Akt phosphorylation. NCT-58 kills the rapidly proliferating bulk tumor cells as well as the breast cancer stem-like population, coinciding with significant reductions in stem/progenitor markers and pluripotent transcription factors. NCT-58 treatment suppressed growth and angiogenesis in a trastuzumab-resistant xenograft model, concomitant with downregulation of ICD-HER2 and HSF-1/HSP70/HSP90. These findings warrant further investigation of NCT-58 to address trastuzumab resistance in heterogeneous HER2-positive cancers.

摘要

正在研发的N端热休克蛋白90（HSP90）抑制剂存在因热休克反应（HSR）诱导和脱靶效应而产生的问题。我们试图研究一种合理合成的C端HSP90抑制剂NCT-58杀死曲妥珠单抗耐药的HER2阳性乳腺癌干细胞样细胞的能力。NCT-58由于靶向C端区域而不诱导HSR，并通过同时下调HER家族成员以及抑制Akt磷酸化来引发抗肿瘤活性。NCT-58杀死快速增殖的大量肿瘤细胞以及乳腺癌干细胞样群体，同时干细胞/祖细胞标志物和多能转录因子显著减少。在曲妥珠单抗耐药的异种移植模型中，NCT-58治疗抑制了肿瘤生长和血管生成，同时下调了ICD-HER2和HSF-1/HSP70/HSP90。这些发现值得对NCT-58进行进一步研究，以解决异质性HER2阳性癌症中的曲妥珠单抗耐药问题。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87fd/8590693/f6c3e7e374ed/41420_2021_743_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87fd/8590693/f6c3e7e374ed/41420_2021_743_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87fd/8590693/e0f15e052794/41420_2021_743_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87fd/8590693/088d1b329c3f/41420_2021_743_Fig2_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87fd/8590693/e926013c657c/41420_2021_743_Fig5_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87fd/8590693/f6c3e7e374ed/41420_2021_743_Fig7_HTML.jpg

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