Abstract 4133: Increased I2PP2A compromises TP53 function by stabilizing MDM2 in Shh medulloblastoma

Abstract

Abstract Medulloblastoma is the most common malignant pediatric brain tumor. Currently, the standard therapy comprising radiation, surgery and chemotherapy “cures” about 70% of medulloblastoma patients. However, these aggressive and non-differential treatment modalities cause lifelong side effects in patients. Medulloblastoma patients are classified into four different subgroups based on transcriptional and molecular profiles, namely WNT, SHH, Group 3, and Group 4. The SHH subgroup accounts for approximately 30% of all medulloblastoma cases and is further subcategorized into TP53 wild type and TP53 deficient subtypes. The importance of TP53 status in SHH medulloblastoma patients has been recently recognized by the association between TP53 mutation and poor prognosis for these patients. However, research findings illustrating TP53 signaling in preclinical models of SHH medulloblastoma are quite limited. Apart from the fact that TP53 mutation is associated with poor survival, 80% of medulloblastoma cases are TP53 wild type. TP53 protein is a tumor suppressor which acts as a checkpoint protein for all types of cells. Cancer cells either mutate TP53 gene or employ other mechanisms such as overexpressing MDM2 to compromise TP53 protein function. Therefore we hypothesize that TP53 function is compromised by highly active MDM2 in TP53 wild type Shh medulloblastoma. Using the SmoA1 mouse model, which closely recapitulates human SHH medulloblastoma, we aim to investigate whether TP53 signaling has been disrupted in Shh medulloblastoma. Surprisingly, we observed relatively higher TP53 protein levels in tumor tissue lysates as compared to that in neighboring normal cerebellum using SmoA1 mice. However, MDM2, the major suppressor of TP53, showed higher phosphorylation at Ser166, which would stabilize MDM2, resulting in degradation of newly-produced TP53 protein. We also found significantly increased protein levels of I2PP2A, an endogenous inhibitor of phosphatase 2A, which can dephosphorylate MDM2 at Ser166. Using COG112, a small molecule inhibitor of I2PP2A, we showed the reactivation of PP2A, concurrent with a decrease of p-MDM2 and an increase of TP53 in a time-dependent manner. From these experiments, we conclude that 1) TP53 pathway is functional in our SmoA1 mouse model; 2) I2PP2A upregulation could be the reason for rapid degradation of TP53 protein in SmoA1 mice. These findings have translational implications as they suggest that targeting I2PP2A in TP53 wild type SHH medulloblastoma patients could be a method of driving tumor cell death, thus resulting in better clinical outcomes for these patients. Citation Format: Yun Wei, Victor Maximov, Anna Kenney. Increased I2PP2A compromises TP53 function by stabilizing MDM2 in Shh medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4133.