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

Soeun Park1,2, Yoon-Jae Kim1,2,3, Jung Min Park1,2

  • 1Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea.

Cell Death Discovery
|November 14, 2021
PubMed

Insights

NCT-58, a novel heat shock protein 90 (HSP90) inhibitor, effectively targets trastuzumab-resistant HER2-positive breast cancer stem cells. It reduces tumor growth and angiogenesis without inducing heat shock response (HSR).

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • N-terminal HSP90 inhibitors face challenges with heat shock response (HSR) induction and off-target effects.
  • Trastuzumab resistance in HER2-positive breast cancer remains a significant clinical problem, particularly in cancer stem-like cells.
  • Targeting HSP90 offers a therapeutic strategy for various cancers, including HER2-positive breast cancer.

Purpose of the Study:

  • To evaluate the efficacy of NCT-58, a C-terminal HSP90 inhibitor, against trastuzumab-resistant HER2-positive breast cancer stem-like cells.
  • To investigate the mechanism of action of NCT-58, including its effect on HSR, HER family members, and Akt phosphorylation.
  • To assess the anti-tumor activity of NCT-58 in preclinical models of trastuzumab-resistant HER2-positive breast cancer.

Main Methods:

  • Synthesis and characterization of NCT-58 as a C-terminal HSP90 inhibitor.
  • In vitro studies assessing NCT-58's effects on breast cancer stem-like cells, HER family members, Akt phosphorylation, and stem/progenitor markers.
  • In vivo evaluation of NCT-58 in a trastuzumab-resistant xenograft model, measuring tumor growth, angiogenesis, and relevant molecular markers.

Main Results:

  • NCT-58 does not induce HSR, unlike N-terminal inhibitors, due to its C-terminal targeting.
  • NCT-58 demonstrated potent anti-tumor activity by downregulating HER family members and inhibiting Akt phosphorylation.
  • NCT-58 effectively killed both bulk tumor cells and cancer stem-like populations, reducing stemness markers and pluripotent transcription factors.
  • In vivo, NCT-58 suppressed tumor growth and angiogenesis in a resistant xenograft model, with downregulation of ICD-HER2 and HSF-1/HSP70/HSP90.

Conclusions:

  • NCT-58 is a promising C-terminal HSP90 inhibitor with a distinct mechanism of action, avoiding HSR induction.
  • NCT-58 exhibits significant anti-cancer activity against trastuzumab-resistant HER2-positive breast cancer, including the stem cell population.
  • Further clinical investigation of NCT-58 is warranted for treating heterogeneous HER2-positive breast cancers with trastuzumab resistance.

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