TrkA activation sustains chemotherapy resistance in chemotolerant medulloblastoma cells.

Medulloblastoma (MB), one of the most common pediatric brain tumors, is reported to resist treatments in almost 30% of cases, allowing for the emergence of fatal recurrences. Thanks to a comprehensive functional and molecular characterization of chemotolerant MB models achieved in a previous study, here we identified neurotrophins (NTRKs) as potential contributors to chemoresistance in MB cells. In this study, we demonstrated that NTRK1 (TrkA) signaling over-activation, identified through available transcriptomic data, negatively correlated with patient survival from public datasets. Specifically, transcriptional data disclosed that TrkA signaling is over-activated in chemoresistant group 3 and 4 MB cells, functionally sustains chemoresistance in vitro, and even correlates with a poor outcome in MB patients. We verified the impact of TrkA signaling manipulation on MB cell survival and chemotherapy sensitivity by stimulating them with NGF or by using NTRK inhibitors. In particular, TrkA receptor activation by NGF was sufficient to promote MB cells’ survival upon chemotherapy treatment. Conversely, both TrkA silencing and its pharmacological inhibition significantly affected MB cell proliferation and survival. More importantly, we demonstrated that TrkA silencing/inhibition was sufficient to sensitize chemoresistant MB cells to treatments and even prevent the emergence of chemotherapy-resistant clones. In conclusion, we demonstrated that TrkA over-activation plays a key role in supporting MB cell survival during treatments and that its specific inhibition may represent a successful therapeutic strategy to sensitize chemotherapy-resistant group 3/4 MB subpopulations to treatments.