Inhibition of the SRC Kinase HCK Impairs STAT3-Dependent Gastric Tumor Growth in Mice

Ashleigh R. Poh, Amy R. Dwyer, Moritz F. Eissmann, Ashwini L. Chand, David Baloyan, Louis Boon, Michael W. Murrey, Lachlan Whitehead, Megan O'Brien, Clifford A. Lowell, Tracy L. Putoczki, Fiona J. Pixley, Robert J.J. O'Donoghue, Matthias Ernst

Research output: Contribution to journalArticle

Abstract

Persistent activation of the latent transcription factor STAT3 is observed in gastric tumor epithelial and immune cells and is associated with a poor patient prognosis. Although targeting STAT3-activating upstream kinases offers therapeutically viable targets with limited specificity, direct inhibition of STAT3 remains challenging. Here we provide functional evidence that myeloid-specific hematopoietic cell kinase (HCK) activity can drive STAT3-dependent epithelial tumor growth in mice and is associated with alternative macrophage activation alongside matrix remodeling and tumor cell invasion. Accordingly, genetic reduction of HCK expression in bone marrow-derived cells or systemic pharmacologic inhibition of HCK activity suppresses alternative macrophage polarization and epithelial STAT3 activation, and impairs tumor growth. These data validate HCK as a molecular target for the treatment of human solid tumors harboring excessive STAT3 activity.

Original languageEnglish
Pages (from-to)428-435
Number of pages8
JournalCancer Immunology Research
Volume8
Issue number4
DOIs
Publication statusPublished - 1 Apr 2020

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    Poh, A. R., Dwyer, A. R., Eissmann, M. F., Chand, A. L., Baloyan, D., Boon, L., ... Ernst, M. (2020). Inhibition of the SRC Kinase HCK Impairs STAT3-Dependent Gastric Tumor Growth in Mice. Cancer Immunology Research, 8(4), 428-435. https://doi.org/10.1158/2326-6066.CIR-19-0623