WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma

摘要

TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/ TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/ TP53 mutant tumours (100% and 36.6%?±?8.7%, respectively (p