Overview
Welcome! We study members of the TAM-family of receptor tyrosine kinases (TYRO3, AXL, and MERTK) in cancer and the effects of TAM inhibition as a disease treatment.
The receptor tyrosine kinase MERTK was first discovered by Dr. Graham and subsequent work in the Graham lab demonstrated oncogenic roles for MERTK in a variety of solid tumor and hematologic malignancies. Current projects focused on acute leukemia, non-small cell lung cancer and melanoma are aimed at better understanding the biology of MERTK and related receptors in tumor cells and their roles in the human immune system.
In addition, we developed and characterized a series of novel small molecules that selectively and potently inhibit MERTK with the goal of targeting MERTK to treat patients with cancer. The lead compound, MRX-2843, is a first-in-class dual MERTK and FLT3-selective tyrosine kinase inhibitor that is currently being tested in phase I clinical trials. Studies to determine the optimal application of MERTK inhibitors in combination with other agents to maximize therapeutic effects are ongoing. We are also working with collaborators to develop additional classes of novel inhibitors targeting the TAM kinases.
Leukemia Projects
- Determine mechanisms of resistance to MERTK inhibition.
- Elucidate molecular pathways that can be targeted in combination with MERTK inhibition to enhance therapeutic efficacy against acute myeloid leukemia (AML).
- Determine oncogenic roles for TYRO3 in AML.
- Develop biomarkers of MERTK inhibition and therapeutic response.
Non-Small Cell Lung Cancer Projects
- Identify tyrosine kinase inhibitors that synergize with MERTK inhibition to suppress tumor growth.
- Determine roles for MERTK in resistance to third-generation EGFR tyrosine kinase inhibitors in non-small cell lung cancers with activating EGFR mutations.
Immuno-Oncology Projects
- Determine immunomodulatory roles for MERTK in the tumor microenvironment using syngeneic mouse models of leukemia, lung cancer, and breast cancer.
- Identify immune biomarkers of MERTK inhibition and therapeutic effects.
- Evaluate roles for MERTK as a mediator of resistance to immune checkpoint blockade.