INVESTIGATING THE ROLE OF TAM (TYRO3, AXL AND MERTK) FAMILY RECEPTORS IN MERLIN-DEFICIENT TUMOURS

Abstract

Mutations in the NF2 gene, which codes for the tumour suppressor Merlin, is responsible for the development of all Neurofibromatosis Type 2 (NF2)-related tumours including schwannomas, meningiomas and ependymomas. These tumours can also occur spontaneously in non-NF2 patients. The only available treatments for this group of tumours are surgery and radiosurgery/radiotherapy. Hence, there is an urgent need for new effective drug-based treatments. TAM (TYRO3, AXL and MERTK) family receptors are involved in tumour development, progression, metastasis and resistance to targeted therapies in several cancers. Our group previously showed overexpression and hyper-activation of all three TAM family receptors and their ligand Gas6 in schwannomas. The key role of AXL in promoting tumour development by altering proliferation, adhesion and survival of human schwannoma primary cells in vitro was also established. The aim of this project is to explore the role of TYRO3 and MERTK in schwannomas’ and all three TAM members in meningiomas’ pathogenesis. Western blotting demonstrated that AXL, MERTK, TYRO3 and their ligand Gas6 are highly expressed and activated in Merlin-deficient meningioma tissues and cells. The expression of AXL, MERTK and TYRO3, but not Gas6, appear to be Merlin-dependent in meningiomas. MERTK forms a complex with TYRO3 but not with AXL in both meningioma and schwannoma tissues, and its expression is mandatory to maintain AXL and TYRO3 levels in both cell-types. MERTK and AXL contribute to increased proliferation and survival of schwannoma and meningioma cells in vitro. MERTK acts via JNK, FAK and cyclin-D1 in meningiomas, and via JNK, AKT, FAK and cyclin-D1 in schwannomas. Pathological proliferation and survival of both cell-types was successfully reversed by AXL inhibitor BGB324 and MERTK inhibitor UNC2025 in vitro, with UNC2025 being more effective. TYRO3 had no effect on cell proliferation of either schwannoma or meningioma cells. In conclusion, AXL and MERTK are important in schwannoma and meningioma pathogenesis and are potentially good therapeutic targets. MERTK inhibitor UNC2025 has the potential to be used as a common candidate for the treatment of NF2-related tumours.