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

32 Citations (Scopus)


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
Issue number1
Publication statusPublished - 2020 Dec

Bibliographical 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: HI12C1852, HA17C0053, HR20C0021), the National Research Foundation (NRF) funded by the Korean government (MSIT) (grant number: 2018R1A2B6005347, 2018R1D1A1B07045416, 2019M3E5D1A01068998), and was supported by a Korea University Guro Hospital grant (grant number: O1904001), and the Brain Korea (BK) 21 Plus Program.

Publisher Copyright:
© 2020, The Author(s).


  • 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


Dive into the research topics of 'A novel HSP90 inhibitor targeting the C-terminal domain attenuates trastuzumab resistance in HER2-positive breast cancer'. Together they form a unique fingerprint.

Cite this