Description
Neurofibromatosis 2-related schwannomatosis (NF2) is a dominantly inherited disorder characterised by inactivation of the neurofibromin 2 gene (NF2) and its tumour suppressor product Merlin (Lloyd and Evans, 2013; Plotkin et al., 2022). Affected individuals are predisposed to nervous system tumours, primarily meningiomas and vestibular schwannomas (VS) (Tiwari and Singh, 2022). NF2-related tumours are more aggressive and recurrent and have worse prognoses than sporadic Merlin-negative tumours (Moyhuddin et al., 2003; Goutagny et al., 2012). All schwannomas and 80% of meningiomas are benign (World Health Organisation [WHO] grade I) but their locations and multiplicity cause early mortality and severe morbidity, including seizures, neurological deficits, hearing loss, and facial paresis (Hexter et al., 2015; Ostrom et al., 2019). These anatomical characteristics also hamper current treatment strategies involving surgery and radiosurgery.Surgery is often highly invasive and may cause facial paralysis and cranial nerve disorder in cases of VS and meningioma, respectively (Vakharia et al., 2012; Ahmeti et al., 2021). Even successful surgeries may not prevent schwannomas recurring at the same grade and meningiomas at higher grades (Lemée, Corniola and Meling, 2020; Sheikh and De Jesus, 2022). Furthermore, though gamma knife is the first-line treatment for cases of VS and unresectable meningiomas, radiosurgery may cause hearing loss and long-term cognitive deficits in each (Day and Halasz, 2017, Haldbo-Classen et al., 2019; Sheikh and De Jesus, 2022). Despite recent improvements in both microsurgery and radiotherapy, deafness is an inevitability for most NF2 patients (Lee et al., 2016). These therapeutic limitations illustrate the urgent need for effective drug-based therapies as a non-invasive means of treating these tumours; currently there are none.
The TYRO3, AXL, and MERTK (TAM) family of tyrosine kinase receptors and their ligand growth arrest-specific protein 6 (Gas6) are overexpressed in numerous solid and haematological cancers including lung, breast, and acute myeloid leukaemia in addition to Merlin-negative schwannomas and meningiomas, and Merlin-positive meningiomas (Png et al., 2011; Graham et al., 2014; Ammoun et al., 2018). TAM receptors are involved in survival, proliferation, metastasis, and drug resistance (Hafizi and Dahlbäck, 2006; Vouri and Hafizi, 2017). For instance, their signalling activity is associated with NF-κB pathway activation which promotes anti-apoptosis and survival (Rogers et al., 2012; Linger et al., 2013). Additionally, Gas6 bridges phosphatidyl serine (PtdSer) on cancer cells and TAM receptors expressed by antigen-presenting cells to skew macrophages towards the anti-inflammatory M2 phenotype, creating a tumour-permissive microenvironment (Ubil et al., 2018). Consequently, several AXL and MERTK inhibitors are being developed to combat various cancers but their use in Merlin-negative tumours is only just being realised (Ammoun et al., 2018; Dave, Ammoun and Hanemann, 2022 [unpublished]).
The present study aimed to bolster MERTK inhibitor UNC2025 as a potential chemotherapeutic agent for NF2-related tumours and elucidate the role of TAM receptors in tumour biology. Our findings demonstrate that MERTK inhibition reduces the proliferation and increases the apoptosis of both Merlin-negative and Merlin-positive meningioma and schwannoma cells. Likewise, reducing the presence of tumour-associated macrophages has a similar effect, reflecting their profound influence on tumour development which can be partially attributed to TAM signalling.
| Period | 2024 |
|---|---|
| Examinee/Supervised Person | Alex Lockley |