Combined inhibition of JAK2-STAT3 and SMO-GLI1/tGLI1 pathways suppresses breast cancer stem cells, tumor growth, and metastasis

Oncogene. 2020 Oct;39(42):6589-6605. doi: 10.1038/s41388-020-01454-1. Epub 2020 Sep 14.

Abstract

Triple-negative breast cancer (TNBC) and HER2-positive breast cancer are particularly aggressive and associated with unfavorable prognosis. TNBC lacks effective treatments. HER2-positive tumors have treatment options but often acquire resistance to HER2-targeted therapy after initial response. To address these challenges, we determined whether novel combinations of JAK2-STAT3 and SMO-GLI1/tGLI1 inhibitors synergistically target TNBC and HER2 breast cancer since these two pathways are concurrently activated in both tumor types and enriched in metastatic tumors. Herein, we show that novel combinations of JAK2 inhibitors (ruxolitinib and pacritinib) with SMO inhibitors (vismodegib and sonidegib) synergistically inhibited in vitro growth of TNBC and HER2-positive trastuzumab-resistant BT474-TtzmR cells. Synergy was also observed against breast cancer stem cells. To determine if the combination is efficacious in inhibiting metastasis, we treated mice with intracardially inoculated TNBC cells and found the combination to inhibit lung and liver metastases, and prolong host survival without toxicity. The combination inhibited orthotopic growth, VEGF-A expression, and tumor vasculature of both TNBC and HER2-positive trastuzumab-refractory breast cancer. Lung metastasis of orthotopic BT474-TtzmR xenografts was suppressed by the combination. Together, our results indicated that dual targeting of JAK2 and SMO resulted in synergistic suppression of breast cancer growth and metastasis, thereby supporting future clinical testing.

Publication types

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

MeSH terms

  • Alternative Splicing
  • Anilides / pharmacology
  • Anilides / therapeutic use
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biphenyl Compounds / pharmacology
  • Biphenyl Compounds / therapeutic use
  • Bridged-Ring Compounds / pharmacology
  • Bridged-Ring Compounds / therapeutic use
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Female
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / metabolism
  • Mice
  • Neoplasm Metastasis / drug therapy
  • Neoplasm Metastasis / pathology
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology
  • Nitriles
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Receptor, ErbB-2 / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects*
  • Smoothened Receptor / antagonists & inhibitors*
  • Smoothened Receptor / metabolism
  • Trastuzumab / pharmacology
  • Trastuzumab / therapeutic use
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / pathology
  • Xenograft Model Antitumor Assays
  • Zinc Finger Protein GLI1 / genetics
  • Zinc Finger Protein GLI1 / metabolism

Substances

  • 11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
  • Anilides
  • Biphenyl Compounds
  • Bridged-Ring Compounds
  • GLI1 protein, human
  • HhAntag691
  • Nitriles
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Pyrimidines
  • SMO protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Smoothened Receptor
  • Zinc Finger Protein GLI1
  • sonidegib
  • ruxolitinib
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • JAK2 protein, human
  • Janus Kinase 2
  • Trastuzumab