JS06.5.A MERTK ON TUMOUR CELLS AND MACROPHAGES: A THERAPEUTIC OPTION FOR NF2-RELATED AND SPORADIC MENINGIOMA

Abstract BACKGROUND Meningioma are common tumours of the nervous system. They occur sporadically or as part of the hereditary NF2-related schwannomatosis syndrome. There is an unmet need for new effective drug treatment. MATERIAL AND METHODS We analysed tumour tissue and used cell culture including 3D cultures and also PDX models applying different functional read outs after pharmacological inhibition and knock down. This was complemented by Western blots, co-IP, RNA seq and proteomic analysis. RESULTS We demonstrate overexpression/activation of TAM (TYRO3/AXL/MERTK) receptors and overexpression/release of ligand GAS6 in patient-derived meningioma tumour cells and tissue. For the first time, we reveal formation of MERTK/TYRO3 heterocomplexes in meningioma. We demonstrate interdependency of TAM receptor expression. We show that MERTK and AXL contribute to increased proliferation and survival of meningioma cells, which we inhibited in vitro using the MERTK/FLT3 inhibitors and the AXL inhibitors. MERTK inhibition was more effective and we show an effect also in 3D tumour models as well as PDX models. Further we found that TAM receptors are expressed by tumour-associated macrophages in meningioma and that MERTK inhibition strongly depleted macrophages in meningioma. CONCLUSION Inhibiting MERTK is a new therapeutic option for meningioma