Tivantinib induces mitotic death in SHH medulloblastoma cell lines.

The c-MET kinase signalling pathway is a key player in the development of the cerebellum and it has been identified as a potential therapeutic candidate for treating medulloblastoma. Here, we confirm that c-MET and its ligand HGF are highly expressed in the SHH medulloblastoma subgroup with SHH-α and SHH-β subtypes showing the highest levels of expression of both genes, respectively. HGF treatments and siRNA-mediated c-MET knockdown demonstrated the proliferative dependance of SHH MB cells on c-MET signalling but time-lapse microscopy revealed heterogeneous behaviours of SHH cell lines after alterations of c-MET levels. Pharmacological inhibition of c-MET signalling established that tivantinib outperforms other c-MET inhibitors, including crizotinib and foretinib, in killing SHH medulloblastoma cells and induces a prolonged block in mitosis followed by apoptotic death in both 2D and 3D cell culture models. We have also shown that tivantinib enhances the anti-proliferative activity of vincristine, standard of care for MB patients, exclusively in DAOY cells where a combination of vincristine and tivantinib selectively increased the level of PARP cleavage. Finally, we demonstrated that foretinib and crizotinib induce mitotic slippage on SHH MB cells and the use of navitoclax, a pan-BCL2 inhibitor, initiates the apoptotic programme after cells fail mitosis. Taken together, these data suggest that tivantinib is a better clinical option for SHH MB patients and foretinib or crizotinib should be only considered in combination with BCL2 inhibitors.