Inhibition of the SRC kinase HCK impairs STAT3-dependent gastric tumor growth in mice.

2020-04

Poh, Ashleigh R

Dwyer, Amy R

Eissmann, Moritz F

Chand, Ashwini L

Baloyan, David

Boon, Louis

Murrey, Michael W

Whitehead, Lachlan

O'Brien, Megan

Lowell, Clifford A

Putoczki, Tracy L

Pixley, Fiona J

O'Donoghue, Robert Jj

Ernst, Matthias

Journal Article

0000-0002-1245-729X

0000-0002-4388-9642

0000-0002-1571-2532

0000-0002-6399-1177

10.1158/2326-6066.CIR-19-0623

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.

link

Cancer Immunology Research 2020; 8(4): 428-435

Cancer immunology research