A novel HSP90 inhibitor targeting the C-terminal domain attenuates trastuzumab resistance in HER2-positive breast cancer

Jung Min Park, Yoon Jae Kim, Soeun Park, Minsu Park, Lee Farrand, Cong Truong Nguyen, Jihyae Ann, Gibeom Nam, Hyun Ju Park, Jeewoo Lee, Ji Young Kim, Jae Hong Seo

Research output: Contribution to journalLetterpeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Article number161
JournalMolecular Cancer
Volume19
Issue number1
DOIs
Publication statusPublished - 2020 Dec

Keywords

  • C-terminal HSP90 inhibitor
  • Cancer stem cells
  • HER2
  • HER2-positive breast cancer
  • NCT-547
  • Trastuzumab resistance
  • p95HER2

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

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