Evaluation of Tumor Cell-Tumor Microenvironment Component Interactions as Potential Predictors of Patient Response to Napabucasin

Mol Cancer Res. 2019 Jul;17(7):1429-1434. doi: 10.1158/1541-7786.MCR-18-1242. Epub 2019 May 1.


Napabucasin is an NAD(P)H:quinone oxidoreductase 1 (NQO1)-bioactivatable small molecule hypothesized to affect multiple oncogenic pathways. In a prespecified, retrospective analysis of the napabucasin phase III CO.23 study, overall survival was longer for napabucasin versus placebo in patients expressing phosphorylated STAT3 (pSTAT3) in tumor cells and cells of the tumor microenvironment (TME). We hypothesized that a connection may exist between NQO1 expression in cancer cells and pSTAT3 in tumor cells and the TME. In 3D spheroid cocultures of cancer cells and cancer-associated fibroblasts, the antitumor activity of napabucasin was NQO1 dependent. The levels of cytokines such as IL6, CXCL10, and GM-CSF were higher in NQO1-positive versus NQO1-deleted cocultures. These differentially secreted cytokines promoted STAT3 phosphorylation in tumor cells and the TME. NQO1-expressing, napabucasin-sensitive tumor cells can modify tumor cells and the TME to promote STAT3 phosphorylation, suggesting that pSTAT3 may be used to identify a subpopulation of patients who would likely respond to napabucasin. IMPLICATIONS: pSTAT3 is a potential biomarker for patient response to the anticancer drug napabucasin.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/7/1429/F1.large.jpg.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzofurans / pharmacology*
  • Cancer-Associated Fibroblasts / drug effects
  • Carcinogenesis / drug effects
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Lineage / drug effects
  • Coculture Techniques
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Hypopharyngeal Neoplasms / drug therapy*
  • Hypopharyngeal Neoplasms / genetics
  • Hypopharyngeal Neoplasms / pathology
  • NAD(P)H Dehydrogenase (Quinone) / genetics*
  • Naphthoquinones / pharmacology*
  • STAT3 Transcription Factor / genetics*
  • Tumor Microenvironment / drug effects


  • Benzofurans
  • Naphthoquinones
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • napabucasin
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human