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Inhibition of a Tyrosine Kinase in Mouse Models Decreased Tumor Growth and Metastasis

By BiotechDaily International staff writers
Posted on 24 Jul 2013
Studies with genetically engineered mouse models of breast cancer, melanoma, and colon cancer have shown that inhibiting the action of the tyrosine kinase MerTK (c-mer proto-oncogene tyrosine kinase) increased the ability of the animals to produce an active immune response and blocked tumor growth and metastasis.

Investigators at the University of North Carolina (Chapel Hill, USA) transplanted tumors into normal mice and into mice that had been genetically engineered to lack the gene for MerTK. MerTK is a member of a receptor tyrosine kinase (RTK) family that also includes AXL and TYRO3. This enzyme is expressed in noncancerous cells found in the tumor microenvironment. It is also ectopically expressed or overexpressed in many hematological and epithelial malignant cells. Expression of MerTK correlates with poor prognosis or chemoresistance in some human tumor types.

Results published in the July 8, 2013, online edition of the Journal of Clinical Investigation revealed that tumors grew slowly and were poorly metastatic in mice lacking the MerTK gene. Transplantation of bone marrow from mice lacking MerTK, but not wild-type bone marrow, into lethally irradiated MMTV-PyVmT mice (a model of metastatic breast cancer) decreased tumor growth and altered cytokine production by tumor CD11b+ cells. Although MerTK expression was not required for tumor infiltration by leukocytes, leukocytes from animals lacking MerTK exhibited lower tumor cell–induced expression of wound healing cytokines and enhanced expression of acute inflammatory cytokines.

These finds show that MerTK signaling promoted tumor growth by dampening acute inflammatory cytokines while inducing wound healing cytokines. These results suggest that inhibition of MerTK in the tumor microenvironment may have clinical benefit, stimulating antitumor immune responses or enhancing immunotherapeutic strategies.

“Our work strongly indicates that if you could inhibit MerTK signaling in the tumor bed, you could trigger a more active immune system leading to a stronger T-cell killing response against the tumor,” said senior author Dr. Shelton Earp, professor of pharmacology and medicine at the University of North Carolina. “We hope to create a new, more MerTK selective tool with which to stimulate the initial tumor response and combine this strategy with existing drugs that extend the immune response. If we can initiate a stronger response and sustain that activity, we may be more effective in treating metastatic cancer. Tumor cells can move throughout the body thwarting some of our best therapeutic interventions. The immune system is mobile and may be able to help eliminate tumor cells even at distant sites.”

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University of North Carolina




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