Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression

Aberrant activation of the SRC family kinase hematopoietic cell kinase (HCK) triggers hematological malignancies as a tumor cell-intrinsic oncogene. Here we find that high HCK levels correlate with reduced survival of colorectal cancer patients. Likewise, increased Hck activity in mice promotes the growth of endogenous colonic malignancies and of human colorectal cancer cell xenografts. Furthermore, tumor-associated macrophages of the corresponding tumors show a pronounced alternatively activated endotype, which occurs independently of mature lymphocytes or of Stat6-dependent Th2 cytokine signaling. Accordingly, pharmacological inhibition or genetic reduction of Hck activity suppresses alternative activation of tumor-associated macrophages and the growth of colon cancer xenografts. Thus, Hck may serve as a promising therapeutic target for solid malignancies. [Display omitted] •Abundant HCK in tumor leukocytes of human colon cancer correlates with poor survival•Excessive myeloid HCK activity results in alternative macrophage polarization•Myeloid HCK promotes colon tumorigenesis associated with increased Stat3 activity•Ablation of HCK or its therapeutic inhibition limits colon cancer xenograft growth Poh et al. show that myeloid-specific Hck activity regulates tumor-associated macrophage polarization, the accumulation of IL-6/IL-11 family cytokines and colon cancer growth. Inhibition of Hck activity reduces tumor burden in mice. In human colorectal cancer, high HCK expression correlates with poor patient outcome.