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

Nataliya Zhukova, Vijay Ramaswamy, Marc Remke, Dianna C Martin, Pedro Castelo-Branco, Cindy H Zhang, Michael Fraser, Ken Tse, Raymond Poon, David JH Shih, Berivan Baskin, Peter N Ray, Eric Bouffet, Peter Dirks, Andre O von Bueren, Elke Pfaff, Andrey Korshunov, David TW Jones, Paul A Northcott, Marcel Kool, Trevor J Pugh, Scott L Pomeroy, Yoon-Jae Cho, Torsten Pietsch, Marco Gessi, Stefan Rutkowski, Laszlo Bognár, Byung-Kyu Cho, Charles G Eberhart, Cecile Faure Conter, Maryam Fouladi, Pim J French, Wieslawa A Grajkowska, Nalin Gupta, Peter Hauser, Nada Jabado, Alexandre Vasiljevic, Shin Jung, Seung-Ki Kim, Almos Klekner, Toshihiro Kumabe, Boleslaw Lach, Jeffrey R Leonard, Linda M Liau, Luca Massimi, Ian F Pollack, Young Shin Ra, Joshua B Rubin, Erwin G Van Meir, Kyu-Chang Wang, William A Weiss, Karel Zitterbart, Robert G Bristow, Benjamin Alman, Cynthia E Hawkins, David Malkin, Steven C Clifford, Stefan M Pfister, Michael D Taylor, Uri Tabori

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<0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (p<0.01)). In contrast, β-catenin mutation sensitized TP53 mutant cells to radiation (p<0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (p<0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.