Hematopoietic cell kinase (HCK) as a therapeutic target in immune and cancer cells
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Ashleigh R. Poh1, Robert J.J. O’Donoghue1,2, Matthias Ernst1,2
1The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Victoria, Australia
2Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Victoria, Australia
Matthias Ernst, e-mail: Matthias.Ernst@ONJCRI.org.au
Keywords: SRC family kinases, hematopoietic cell kinase, cancer, leukemia, SFK inhibitors
Received: April 01, 2015 Accepted: May 29, 2015 Published: June 10, 2015
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.
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