Abstract 2798: Identification of gamma secretase inhibitor (GSI)-responsive GBM patients: Involvement of NOTCH, p53, and PI3K/MAPK signaling
Authors: Zhang Chen , Juan Martinez-Ledesma , Ding Jie , Gao Feng , Wu Shaofang , Li Xiaolong , Sulman Erik Philip , Koul Dimpy , Yung WK Alfred 
Published: July 2017

Glioblastoma (GBM) is the most common and lethal primary intracranial tumor. The recent standard-of-care treatment consisting of surgery, followed by radiotherapy and temozolomide, just prolongs the median survival period of GBM patients to 14.6 months. What impedes the survival is due to the extensive heterogeneity among GBM patients at both the cellular and the molecular levels. In our study, we focused on the precision medicine strategy targeting NOTCH signaling. According to recent Phase I/II clinical trial results, only a few GBM patients showed satisfactory response to GSIs. However, little is known regarding how to distinguish GSI-responsive patients. Here, we illustrated that it required (1) high NOTCH activity, (2) wild-type p53 and elevated P53 activity, (3) increased MAPK activity, and (4) decreased PI3K/AKT activity for GBM to respond to GSIs. In our study, we tested a series of patient-derived primary glioma stem cells (GSCs) to two GSIs (RO4929097 and BMS-708163). GSI-sensitive lines were identified and GSI compounds impaired cell viability and sphere formation ability in these cell lines. GSIs also induced cell death of the sensitive GSCs. To find out the signature of the GSI-sensitive GSCs, we did enrichment and correlation analyses against RNA sequencing, RPPA, and methylation data of the GSI-sensitive and resistant GBM lines. We found that GSI-sensitive GSCs harbored significantly elevated Notch activity (high NOTCH1 and NICD1 expression, and low Notch1 methylation). Interestingly, GSI-responsive cells also possessed increased P53 activity (increased expression of P53 targets-P21, BAX and TIGAR), high wild-type p53 frequencies, increased MAPK activity (elevated p-Erk1/2-Thr202/Tyr204 expression), and decreased PI3K/AKT activity (high PTEN expression and low p-AKT-Thr308, RAPTOR, p-4E-BP1-Ser65 expression) (P&lt;0.05). In an attempt to strengthen GSI effect, we showed that MDM2 inhibitor Nutlin-3 (retards P53 degradation and increases P53 activity) combining RO4929097 exhibited synergistic effect on suppressing cell viability of GSI-sensitive cells with wild-type p53. In summary, we elucidated the genetic characteristics (high NOTCH, wild-type p53, high MAPK, and low PI3K/AKT) of GSI sensitive GSCs. Co-administration of Nutlin-3 enhanced GSI function in the subset of GBMs. Our findings indicated genetic markers could be used to identify patients responsive to GSIs, providing a new therapeutic strategy to treat this population of GBM patients.

Citation Format: Chen Zhang, Martinez-Ledesma Juan, Jie Ding, Feng Gao, Shaofang Wu, Xiaolong Li, Erik Philip Sulman, Dimpy Koul, WK Alfred Yung. Identification of gamma secretase inhibitor (GSI)-responsive GBM patients: Involvement of NOTCH, p53, and PI3K/MAPK signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2798. doi:10.1158/1538-7445.AM2017-2798