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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis / drug effects
  • Casein Kinase II / antagonists & inhibitors
  • Casein Kinase II / chemistry
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Dyrk Kinases
  • Humans
  • Mice
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / pathology
  • Nitrobenzenes / chemistry
  • Nitrobenzenes / pharmacology
  • Nitrobenzenes / therapeutic use*
  • Paclitaxel / pharmacology
  • Paclitaxel / therapeutic use
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / chemistry
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / chemistry
  • Thiazines / chemistry
  • Thiazines / pharmacology
  • Thiazines / therapeutic use*
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Nitrobenzenes
  • Protein Kinase Inhibitors
  • Thiazines
  • multi-kinase inhibitor 108600
  • Protein-Tyrosine Kinases
  • CSNK2A1 protein, human
  • Casein Kinase II
  • Protein Serine-Threonine Kinases
  • TNIK protein, human
  • Paclitaxel