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

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...

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Autores principales:	Soeun Park, Yoon-Jae Kim, Jung Min Park, Minsu Park, Kee Dal Nam, Lee Farrand, Cong-Truong Nguyen, Minh Thanh La, Jihyae Ann, Jeewoo Lee, Ji Young Kim, Jae Hong Seo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
Acceso en línea:	https://doaj.org/article/5abd2556d6fa4f7bb936d8f0108b8169
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spelling	oai:doaj.org-article:5abd2556d6fa4f7bb936d8f0108b81692021-11-14T12:12:32ZThe C-terminal HSP90 inhibitor NCT-58 kills trastuzumab-resistant breast cancer stem-like cells10.1038/s41420-021-00743-22058-7716https://doaj.org/article/5abd2556d6fa4f7bb936d8f0108b81692021-11-01T00:00:00Zhttps://doi.org/10.1038/s41420-021-00743-2https://doaj.org/toc/2058-7716Abstract 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.Soeun ParkYoon-Jae KimJung Min ParkMinsu ParkKee Dal NamLee FarrandCong-Truong NguyenMinh Thanh LaJihyae AnnJeewoo LeeJi Young KimJae Hong SeoNature Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282CytologyQH573-671ENCell Death Discovery, Vol 7, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671 Soeun Park Yoon-Jae Kim Jung Min Park Minsu Park Kee Dal Nam Lee Farrand Cong-Truong Nguyen Minh Thanh La Jihyae Ann Jeewoo Lee Ji Young Kim Jae Hong Seo The C-terminal HSP90 inhibitor NCT-58 kills trastuzumab-resistant breast cancer stem-like cells
description	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.
format	article
author	Soeun Park Yoon-Jae Kim Jung Min Park Minsu Park Kee Dal Nam Lee Farrand Cong-Truong Nguyen Minh Thanh La Jihyae Ann Jeewoo Lee Ji Young Kim Jae Hong Seo
author_facet	Soeun Park Yoon-Jae Kim Jung Min Park Minsu Park Kee Dal Nam Lee Farrand Cong-Truong Nguyen Minh Thanh La Jihyae Ann Jeewoo Lee Ji Young Kim Jae Hong Seo
author_sort	Soeun Park
title	The C-terminal HSP90 inhibitor NCT-58 kills trastuzumab-resistant breast cancer stem-like cells
title_short	The C-terminal HSP90 inhibitor NCT-58 kills trastuzumab-resistant breast cancer stem-like cells
title_full	The C-terminal HSP90 inhibitor NCT-58 kills trastuzumab-resistant breast cancer stem-like cells
title_fullStr	The C-terminal HSP90 inhibitor NCT-58 kills trastuzumab-resistant breast cancer stem-like cells
title_full_unstemmed	The C-terminal HSP90 inhibitor NCT-58 kills trastuzumab-resistant breast cancer stem-like cells
title_sort	c-terminal hsp90 inhibitor nct-58 kills trastuzumab-resistant breast cancer stem-like cells
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/5abd2556d6fa4f7bb936d8f0108b8169
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The C-terminal HSP90 inhibitor NCT-58 kills trastuzumab-resistant breast cancer stem-like cells

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