Targeting MERTK on tumour cells and macrophages: a potential intervention for sporadic and NF2-related meningioma and schwannoma tumours

Foram Dave; Kevin Herrera; Alex Lockley; Laurien L van de Weijer; Summer Henderson; Agbolahan A Sofela; Laura Hook; Claire L Adams; Emanuela Ercolano; David A Hilton; Emmanuel A Maze; Kathreena M Kurian; Sylwia Ammoun; C Oliver Hanemann

doi:10.1038/s41388-024-03131-z

Targeting MERTK on tumour cells and macrophages: a potential intervention for sporadic and NF2-related meningioma and schwannoma tumours

Oncogene. 2024 Oct;43(41):3049-3061. doi: 10.1038/s41388-024-03131-z. Epub 2024 Aug 23.

Affiliations

¹ University of Plymouth, Faculty of Health, The John Bull Building, Plymouth Science Park, Research Way, Plymouth, PL6 8BU, UK.
² Department of Cellular and Anatomical Pathology, University Hospitals Plymouth NHS Trust, Derriford, Plymouth, PL6 8DH, UK.
³ University of Bristol Medical School & North Bristol Trust, Southmead Hospital, Bristol, BS1 0NB UK, Bristol, BS1 0NB, UK.
⁴ University of Plymouth, Faculty of Health, The John Bull Building, Plymouth Science Park, Research Way, Plymouth, PL6 8BU, UK. [email protected].
⁵ University of Plymouth, Faculty of Health, The John Bull Building, Plymouth Science Park, Research Way, Plymouth, PL6 8BU, UK. [email protected].

^# Contributed equally.

Abstract

Meningioma and schwannoma 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 treatments for both tumour types. In this paper, we demonstrate overexpression/activation of TAM (TYRO3/AXL/MERTK) receptors (TAMs) and overexpression/release of ligand GAS6 in patient-derived meningioma tumour cells and tissue. For the first time, we reveal the formation of MERTK/TYRO3 heterocomplexes in meningioma and schwannoma tissue. We demonstrate the dependence of AXL and TYRO3 expression on MERTK in both tumour types, as well as interdependency of MERTK and AXL expression in meningioma. We show that MERTK and AXL contribute to increased proliferation and survival of meningioma and schwannoma cells, which we inhibited in vitro using the MERTK/FLT3 inhibitor UNC2025 and the AXL inhibitor BGB324. UNC2025 was effective in both tumour types with superior efficacy over BGB324. Finally, we found that TAMs are expressed by tumour-associated macrophages in meningioma and schwannoma tumours and that UNC2025 strongly depleted macrophages in both tumour types.

MeSH terms

Adenine / analogs & derivatives
Axl Receptor Tyrosine Kinase*
Benzocycloheptenes / pharmacology
Cell Line, Tumor
Cell Proliferation
Humans
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism
Macrophages* / metabolism
Macrophages* / pathology
Meningeal Neoplasms* / drug therapy
Meningeal Neoplasms* / genetics
Meningeal Neoplasms* / metabolism
Meningeal Neoplasms* / pathology
Meningioma* / genetics
Meningioma* / metabolism
Meningioma* / pathology
Neurilemmoma* / genetics
Neurilemmoma* / metabolism
Neurilemmoma* / pathology
Neurofibromatosis 2 / genetics
Neurofibromatosis 2 / metabolism
Neurofibromatosis 2 / pathology
Neurofibromin 2 / genetics
Neurofibromin 2 / metabolism
Piperazines
Proto-Oncogene Proteins* / antagonists & inhibitors
Proto-Oncogene Proteins* / genetics
Proto-Oncogene Proteins* / metabolism
Receptor Protein-Tyrosine Kinases* / genetics
Receptor Protein-Tyrosine Kinases* / metabolism
Triazoles
c-Mer Tyrosine Kinase* / genetics
c-Mer Tyrosine Kinase* / metabolism

Substances

c-Mer Tyrosine Kinase
MERTK protein, human
Receptor Protein-Tyrosine Kinases
Axl Receptor Tyrosine Kinase
Proto-Oncogene Proteins
growth arrest-specific protein 6
Neurofibromin 2
UNC2025
bemcentinib
NF2 protein, human
TYRO3 protein, human
AXL protein, human
Intercellular Signaling Peptides and Proteins
Benzocycloheptenes
Adenine
Piperazines
Triazoles

Grants and funding

AFR19-20366/Animal Free Research UK