The C-terminal HSP90 Inhibitor NCT-58 Kills Trastuzumab-resistant Breast Cancer Stem-like Cells

Overview

Journal Cell Death Discov

Date 2021 Nov 14

PMID 34775489

Citations 11

Authors

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

Affiliations

Soon will be listed here.

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.

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