Standard treatment against paediatric BRAF-V600E glioma promotes senescence and sensitizes tumours to BCL-xL inhibition
Romain Guiho, Hiba Hamdi, Grace Cooksley, Timoty H Chang, Lei Cao, Romain Sigaud, Sophie Bliss, Ashley Vardon, Scott Haston, Florian Selt, Akang Leonard Bassey, Daniela Kocher, Ria Kedia, Daniel Gharai, Jesús Gil, Olaf Witt, Till Milde, Darren Hargrave, Paula Alexandre, Pratiti Bandopadhayay, Juan Pedro Martinez BarberaAbstract
Background
Chemo-, radio-, and targeted therapies can induce a stable growth arrest known as therapy-induced senescence (TIS), which may be therapeutically exploited using senolytic compounds that selectively eliminate senescent cells. Children with BRAF-V600E-driven brain tumours are commonly treated with low-dose chemotherapies and MAPK inhibitors, alone or in combination, often with good initial responses. However, a majority of patients experiences tumour regrowth following treatment withdrawal. Here, we investigate the contribution of TIS to treatment response and relapse, and assess the therapeutic potential of senolytics in preclinical models of paediatric BRAF-V600E glioma.
Methods
Preclinical models of paediatric low-grade glioma were analysed in vitro or following orthotopic transplantation into mice and treated with Dabrafenib, Trametinib, Tovorafenib or Vinblastine. Senescence was assessed using molecular and cytological markers. Sensitivity to senolytic compounds was evaluated using in vitro dose-response assays and in vivo treatment studies.
Results
Trametinib induced a robust senescent phenotype in BT-40 tumours in vivo, characterised by activation of a senescence-associated secretory phenotype and expansion of IBA-1-positive myeloid cells. In vitro, senescence was induced in BT-40 cells following treatment with MAPK inhibitors and Vinblastine, and was similarly observed in H9-derived human neural stem cells expressing BRAF-V600E. Navitoclax was identified as a potent senolytic against senescent BT-40 cells, primarily through inhibition of the anti-apoptotic protein BCL-xL. In vivo, combined Trametinib and Navitoclax treatment ablated senescent tumour cells, significantly reduced tumour regrowth after treatment withdrawal, and improved survival.
Conclusions
These findings demonstrate that Navitoclax enhances Trametinib's anti-tumour efficacy and limits tumour relapse following treatment cessation.