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Mol Cancer Res. 2019 May 1. pii: molcanres.1242.2019. doi: 10.1158/1541-7786.MCR-18-1242. [Epub ahead of print]

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

Author information

1
Research and Discovery, Boston Biomedical Inc.
2
Boston Biomedical Inc.
3
Discovery Research, Boston Biomedical Inc.
4
Boston Biomedical Inc. HRogoff@bostonbiomedical.com.

Abstract

Napabucasin is an 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 co-cultures of cancer cells and cancer-associated fibroblasts, the anti-tumor 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 co-cultures. These differentially secreted cytokines promoted STAT3 phosphorylation in tumor cells and the TME. Implications: 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 be likely respond to napabucasin. Implications: Phosphorylated STAT3 is a potential biomarker for patient response to the anticancer drug napabucasin.

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