Abstract 4164: TRAIL resistance of glioblastoma cells is associated with DNA damage signalling network

Abstract

To reduce the risk of ageing associated dysfunctions and maintain the genomic stability, cells need a complex DNA repair mechanisms. Defects in this pathway or accumulation of DNA damage lead to genome instability, tumorigenesis, and ageing. Chemotherapy and radiotherapy are designed to kill cancer cells by inducing DNA damage and triggering cellular ageing. Surgery followed by combined chemotherapy and radiotherapy is currently the standard therapy for glioblastoma multiforme (GBM) which is the most common primary brain tumor. TNF related apoptosis-inducing ligand (TRAIL) is promising anti-cancer agent for GBM therapy, as it induces apoptotic death in only cancerous cells, but not in normal cells. However, the mechanisms underlying TRAIL resistance in GBM have remained elusive. To understand the role of DNA damage response (DDR) mechanism and develop more effective therapeutic approaches, TRAIL resistant and sensitive T98G cells were generated. The effect of DDR proteins (H2AX (Ser319), ATM total, ATR total, CHK1 total, CHK2 total, ATM (Ser1981), ATR (Ser428), CHK1 (Ser345), CHK2 (Ser19) and 53BP1) on TRAIL resistance was detected in TRAIL resistant and sensitive T98G cells. These proteins showed different level of protein expressions in TRAIL resistance and sensitive T98G cells. Most remarkable difference was found in the level of phosphorylated kinase CHK2 (Ser19) with higher expression level in TRAIL resistant T98G cells than TRAIL sensitive T98G cells. Therapies that inhibit CHK2 (Ser19) levels in glioma may enhance the efficacy of TRAIL treatment. In immunofluorescence analysis, increased number of γH2AX foci was noted upon TRAIL treatment. These findings demonstrate that DNA damage signalling pathways contribute to TRAIL resistance and targeted inhibition of DNA repair factors can provide the most effective therapeutic strategies to overcome TRAIL resistance of GBMs. Moreover, the information from this study may hold answers for cancer research in future and serve as a potential suppressor for the treatment of cancer. Citation Format: İlknur Sur, Kerem Muslu, Ahmet Cingöz, Tuğba Bağcı Önder. TRAIL resistance of glioblastoma cells is associated with DNA damage signalling network [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 4164. doi:10.1158/1538-7445.AM2017-4164

Overcoming TRAIL Resistance for Glioblastoma Treatment

“…Remarkable differences have been observed in levels of proteins pivotal for DNA damage response between TRAIL-sensitive and -resistant GBM cells, such as ATM and CHK2. Therapies that inhibit CHK2 levels in GBM may enhance the efficacy of TRAIL treatment, hinting that DNA damage signaling pathways might contribute to TRAIL resistance and that targeting DNA repair factors is a strategy to overcome TRAIL resistance of GBM [ 104 ].…”