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

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

doi:10.1038/s41420-021-00743-2

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

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

Department of Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

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.

Original language	English
Article number	354
Journal	Cell Death Discovery
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41420-021-00743-2
Publication status	Published - 2021 Dec

ASJC Scopus subject areas

Immunology
Cellular and Molecular Neuroscience
Cell Biology
Cancer Research

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10.1038/s41420-021-00743-2

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title = "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 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.",

author = "Soeun Park and Kim, {Yoon Jae} and Park, {Jung Min} and Minsu Park and Nam, {Kee Dal} and Lee Farrand and Nguyen, {Cong Truong} and La, {Minh Thanh} and Jihyae Ann and Jeewoo Lee and Kim, {Ji Young} and Seo, {Jae Hong}",

note = "Funding Information: This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HA17C0053, HR20C0021), the National Research Foundation (NRF) funded by the Korean government (MSIT) (grant number: 2019M3E5D1A01068998, 2021R1A2C2009723, 2021R1I1A1A01045588), and was supported by the Brain Korea (BK) 21 Plus Program. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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doi = "10.1038/s41420-021-00743-2",

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AU - Park, Soeun

AU - Kim, Yoon Jae

AU - Park, Jung Min

AU - Park, Minsu

AU - Nam, Kee Dal

AU - Farrand, Lee

AU - Nguyen, Cong Truong

AU - La, Minh Thanh

AU - Ann, Jihyae

AU - Lee, Jeewoo

AU - Kim, Ji Young

AU - Seo, Jae Hong

N1 - Funding Information: This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HA17C0053, HR20C0021), the National Research Foundation (NRF) funded by the Korean government (MSIT) (grant number: 2019M3E5D1A01068998, 2021R1A2C2009723, 2021R1I1A1A01045588), and was supported by the Brain Korea (BK) 21 Plus Program. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

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

Abstract

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