Targeting STAT3 by a small molecule suppresses pancreatic cancer progression

Oncogene. 2021 Feb;40(8):1440-1457. doi: 10.1038/s41388-020-01626-z. Epub 2021 Jan 8.

Abstract

Pancreatic cancer is lethal in over 90% of cases since it is resistant to current therapeutic strategies. The key role of STAT3 in promoting pancreatic cancer progression has been proven, but effective interventions that suppress STAT3 activities are limited. The development of novel anticancer agents that directly target STAT3 may have potential clinical benefits for pancreatic cancer treatment. Here, we report a new small-molecule inhibitor (N4) with potent antitumor bioactivity, which inhibits multiple oncogenic processes in pancreatic cancer. N4 blocked STAT3 and phospho-tyrosine (pTyr) peptide interactions in fluorescence polarization (FP) assay, specifically abolished phosphor-STAT3 (Tyr705), and suppressed expression of STAT3 downstream genes. The mechanism involved the direct binding of N4 to the STAT3 SH2 domain, thereby, the STAT3 dimerization, STAT3-EGFR, and STAT3-NF-κB cross-talk were efficiently inhibited. In animal models of pancreatic cancer, N4 was well tolerated, suppressed tumor growth and metastasis, and significantly prolonged survival of tumor-bearing mice. Our results offer a preclinical proof of concept for N4 as a candidate therapeutic compound for pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • ErbB Receptors / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mice
  • NF-kappa B / genetics
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • STAT3 Transcription Factor / genetics*
  • Signal Transduction / drug effects
  • Small Molecule Libraries / pharmacology*
  • Xenograft Model Antitumor Assays
  • src Homology Domains / genetics

Substances

  • NF-kappa B
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Small Molecule Libraries
  • EGFR protein, human
  • ErbB Receptors