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Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease

Author

Listed:
  • Katsutoshi Sato

    (Icahn School of Medicine at Mount Sinai)

  • Amol A. Padgaonkar

    (Icahn School of Medicine at Mount Sinai)

  • Stacey J. Baker

    (Icahn School of Medicine at Mount Sinai)

  • Stephen C. Cosenza

    (Icahn School of Medicine at Mount Sinai)

  • Olga Rechkoblit

    (Icahn School of Medicine at Mount Sinai)

  • D. R. C. Venkata Subbaiah

    (Icahn School of Medicine at Mount Sinai)

  • Josep Domingo-Domenech

    (Thomas Jefferson University)

  • Alison Bartkowski

    (Icahn School of Medicine at Mount Sinai)

  • Elisa R. Port

    (Mount Sinai Hospital)

  • Aneel K. Aggarwal

    (Icahn School of Medicine at Mount Sinai)

  • M. V. Ramana Reddy

    (Icahn School of Medicine at Mount Sinai)

  • Hanna Y. Irie

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • E. Premkumar Reddy

    (Icahn School of Medicine at Mount Sinai)

Abstract

Triple negative breast cancer (TNBC) remains challenging because of heterogeneous responses to chemotherapy. Incomplete response is associated with a greater risk of metastatic progression. Therefore, treatments that target chemotherapy-resistant TNBC and enhance chemosensitivity would improve outcomes for these high-risk patients. Breast cancer stem cell-like cells (BCSCs) have been proposed to represent a chemotherapy-resistant subpopulation responsible for tumor initiation, progression and metastases. Targeting this population could lead to improved TNBC disease control. Here, we describe a novel multi-kinase inhibitor, 108600, that targets the TNBC BCSC population. 108600 treatment suppresses growth, colony and mammosphere forming capacity of BCSCs and induces G2M arrest and apoptosis of TNBC cells. In vivo, 108600 treatment of mice bearing triple negative tumors results in the induction of apoptosis and overcomes chemotherapy resistance. Finally, treatment with 108600 and chemotherapy suppresses growth of pre-established TNBC metastases, providing additional support for the clinical translation of this agent to clinical trials.

Suggested Citation

  • Katsutoshi Sato & Amol A. Padgaonkar & Stacey J. Baker & Stephen C. Cosenza & Olga Rechkoblit & D. R. C. Venkata Subbaiah & Josep Domingo-Domenech & Alison Bartkowski & Elisa R. Port & Aneel K. Aggarw, 2021. "Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24878-z
    DOI: 10.1038/s41467-021-24878-z
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