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

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

  • Nat Commun. 2021 Aug 3;12(1):4671. doi: 10.1038/s41467-021-24878-z.
Katsutoshi Sato # 1,  Amol A Padgaonkar # 2,  Stacey J Baker 2,  Stephen C Cosenza 2,  Olga Rechkoblit 3,  D R C Venkata Subbaiah 2,  Josep Domingo-Domenech 4,  Alison Bartkowski 1,  Elisa R Port 5,  Aneel K Aggarwal 3,  M V Ramana Reddy 2,  Hanna Y Irie 6 7,  E Premkumar Reddy 8
Affiliations

Affiliations

  • 1 Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 2 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 3 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 4 Medical Oncology and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
  • 5 Department of Surgery, Mount Sinai Hospital, New York, NY, USA.
  • 6 Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. hanna.irie@mssm.edu.
  • 7 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. hanna.irie@mssm.edu.
  • 8 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ep.reddy@mssm.edu.
  • # Contributed equally.
PMID: 34344863 DOI: 10.1038/s41467-021-24878-z
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.

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