CITK Loss Inhibits Growth of Group 3 and Group 4 Medulloblastoma Cells and Sensitizes Them to DNA-Damaging Agents

Medulloblastoma (MB) is the most common pediatric brain tumor and it is classified into four biological subgroups: WNT, SHH, Group 3 and Group 4. MB is currently treated with surgery, followed by irradiation (IR) and high-dose multi-agent chemotherapy. Despite recent progress, Group 3 and Group 4 MB are is still associated to relatively high lethality and dramatic neurological and endocrine side effects. Therefore, more effective therapies are needed. Citron kinase (CITK) has been proposed as a promising target for SHH MB, since its inactivation leads to reduction of tumor growth, induction of DNA damage and apoptosis. During my master thesis we assessed the effects of CITK loss in Group 3/ Group 4 MB cell lines D283 and D341. CITK depletion impaired proliferation, induced cytokinesis failure and apoptosis. Moreover, CITK knockdown produced an accumulation of DNA damage, with reduced RAD51 levels and an impairment in homologous recombination. Lastly, we found that the association of IR or cisplatin with CITK depletion strongly impaired the growth potential of Group3/Group 4 and SHH MB cells. These results indicate that CITK inactivation could prevent the expansion of MB cells and increase their sensitivity to DNA-damaging agents. We suggest that CITK inhibition could be broadly associated with IR and adjuvant therapy in MB treatment.