The
hematopoietic cell kinase (HCK) is a member of the SRC family of cytoplasmic
tyrosine kinases (SFKs), and is expressed in cells of the myeloid and B-lymphocyte cell lineages. Excessive HCK activation is associated with several types of
leukemia and enhances cell proliferation and survival by physical association with oncogenic fusion
proteins, and with functional interactions with
receptor tyrosine kinases. Elevated HCK activity is also observed in many solid
malignancies, including breast and
colon cancer, and correlates with decreased patient survival rates. HCK enhances the secretion of
growth factors and pro-inflammatory
cytokines from myeloid cells, and promotes macrophage polarization towards a wound healing and
tumor-promoting alternatively activated phenotype. Within tumor associated macrophages, HCK stimulates the formation of podosomes that facilitate extracellular matrix degradation, which enhance immune and epithelial cell invasion. By virtue of functional cooperation between HCK and bona fide oncogenic
tyrosine kinases, excessive HCK activation can also reduce
drug efficacy and contribute to chemo-resistance, while genetic ablation of HCK results in minimal physiological consequences in healthy mice. Given its known crystal structure, HCK therefore provides an attractive therapeutic target to both, directly inhibit the growth of
cancer cells, and indirectly curb the source of
tumor-promoting changes in the tumor microenvironment.