DRES-02. PARYLATION OF MGMT BY PARP IS REQUIRED FOR MGMT MEDIATED TEMOZOLOMIDE-INDUCED O6-METHYLGUANINE REPAIR: A NOVEL MECHANISM OF MGMT ACTION. (11th November 2019)

• Record Type: Journal Article
• Authors: Wu, Shaofang; Gao, Feng; Koul, Dimpy; Yung, Alfred
• Is Part Of: Neuro-oncology. Volume 21(2019)Supplement 6
• Page Start: vi71
• Page End: vi72
• Publication Date: 2019-11-11
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noz175.290
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Temozolomide (TMZ) is the standard chemotherapy for malignant gliomas (MG), and resistance to this drug is mediated by the DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT). Epigenetic silencing of the MGMT gene by promoter methylation in about 40% patients is associated with loss of MGMT expression that compromises DNA repair leading to favorable response to TMZ therapy. Understanding the mechanism of MGMT mediated repair and modulating MGMT activity will enhance TMZ activity in MGMT unmethylated MG. Here we report a novel mode of regulation of MGMT protein activity by Poly-ADP-ribose polymerase (PARP). We found that PAPR physically interacts with MGMT and PARylates MGMT in response to TMZ treatment. We further showed PARylation of MGMT by PAPR is required for MGMT binding to DNA and to remove O 6 -methylguanine adducts in damaged DNA induced by TMZ. All 4 PARP inhibitors (trapping and non-trapping) tested (Talazoparib, Pamiparib, Veliparib, Olaparib) can inhibit PARP-MGMT binding, PARylation of MGMT, binding to DNA and subsequent removal of O 6 - lesions in damaged DNA. We showed combination of PARP inhibitor with TMZ potentiated TMZ cytotoxicity in both MGMT methylated and unmethylated Glioma stem cell lines, but more profoundly in unmethylated group in vitro and in vivo. PARP inhibition acted as a double-edged sword in MGMT unmethylated MG: blocking BER/SSBR pathway to repair TMZ induced N 7 -MetG and O 3 -MetA, and more importantly, suppressing PARP-mediated PARylation of MGMT and thus silencing MGMT activity to repair O 6 -MetG, resulting in augmented cytotoxicity. This is the first study to show that PARylation of MGMT by PARP is required for repairing TMZ-induced O 6 -methylguanine adducts, and inhibition of MGMT PARylation abolishes MGMT function and renders sensitization to TMZ treatment. This finding provides a rationale for combining TMZ/CCNU and PARP inhibitors in MGMT unmethylated MG patients to enhance the benefit of adjuvant chemotherapy.