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

  • Cell Death Discov. 2021 Nov 13;7(1):354. doi: 10.1038/s41420-021-00743-2.
Soeun Park   #  1  2 ,  Yoon-Jae Kim   #  1  2  3 ,  Jung Min Park  1  2 ,  Minsu Park  1  2 ,  Kee Dal Nam  1  3 ,  Lee Farrand  4 ,  Cong-Truong Nguyen  5 ,  Minh Thanh La  5 ,  Jihyae Ann  5 ,  Jeewoo Lee  6 ,  Ji Young Kim  7  8 ,  Jae Hong Seo  9  10  11
Affiliations
  • 1. Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea.
  • 2. Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea.
  • 3. Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul, 08308, Republic of Korea.
  • 4. Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, 5000, Australia.
  • 5. Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
  • 6. Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. [email protected].
  • 7. Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea. [email protected].
  • 8. Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul, 08308, Republic of Korea. [email protected].
  • 9. Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea. [email protected].
  • 10. Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea. [email protected].
  • 11. Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul, 08308, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 34775489 DOI: 10.1038/s41420-021-00743-2
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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