Inhibition of the SRC kinase HCK impairs STAT3-dependent gastric tumor growth in mice
- Poh, AR; Dwyer, AR; Eissmann, MF; Chand, AL; Baloyan, D; Boon, L; Murrey, MW; Whitehead, L; O'Brien, M; Lowell, CA; Putoczki, TL; Pixley, FJ; O'Donoghue, RJ; Ernst, M;
- Journal Title
- Cancer Immunology Research
- Publication Type
- Journal epub ahead of print
- 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, 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.
- WEHI Research Division(s)
- Advanced Technology And Biology; Personalised Oncology
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2020-05-04 11:46:56Last Modified: 2020-05-04 02:24:37