The Graham lab focuses much of its research on the role of Mer and Axl receptor tyrosine kinases(RTKs) in development and progression of human cancer. Mer is overexpressed in multiple human cancers and is transforming in vitro. With a particular focus on leukemia, lymphoma, and non-small cell lung cancer, the Graham lab has elucidated pro-survival pathways which are activated as a result of abnormal Mer and Axl activation. Specifically, the abnormal expression of Mer and/ or Axl leads to downstream activation of AKT and ERK 1/2 and mTOR, allowing cancer cells to survive even in the presence of apoptotic stimuli. In solid tumors, the Mer and Axl RTKs are important in cancer cell invasion. Using shRNA knockdown of Mer, a prolongation of survival has been found in xenograft studies. Recently, novel biologic inhibitors of Mer and Axl have been developed in the Graham lab and are being tested in preclinical in vitro and in vivo studies.
The Graham also studies the role of Mer and Axl in normal cellular functions. Recently, a truncated and soluble from of Mer (sMer) has been discovered which binds and sequesters the Mer/Axl ligand Gas6, thus preventing activation of membrane-bound Mer. Thus, sMer regulates Mer and Axl’s role in macrophage clearance of apoptotic cells and in platelet aggregation/clot formation. Current investigations are testing the potential use of sMer as a therapeutic agent in the treatment of patients with clotting disorders.