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The Versatile Attributes of MGMT: Its Repair Mechanism, Crosstalk with Other DNA Repair Pathways, and Its Role in Cancer.

ABSTRACT: O⁶-methylguanine-DNA methyltransferase (MGMT or AGT) is a DNA repair protein with the capability to remove alkyl groups from O⁶-AlkylG adducts. Moreover, MGMT plays a crucial role in repairing DNA damage induced by methylating agents like temozolomide and chloroethylating agents such as carmustine, and thereby contributes to chemotherapeutic resistance when these agents are used. This review delves into the structural roles and repair mechanisms of MGMT, with emphasis on the potential structural and functional roles of the N-terminal domain of MGMT. It also explores the development of cancer therapeutic strategies that target MGMT. Finally, it discusses the intriguing crosstalk between MGMT and other DNA repair pathways.

SUBMITTER: Fang Q

PROVIDER: S-EPMC10814553 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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The Versatile Attributes of MGMT: Its Repair Mechanism, Crosstalk with Other DNA Repair Pathways, and Its Role in Cancer.

Fang Qingming Q

Cancers 20240111 2

O<sup>6</sup>-methylguanine-DNA methyltransferase (MGMT or AGT) is a DNA repair protein with the capability to remove alkyl groups from O<sup>6</sup>-AlkylG adducts. Moreover, MGMT plays a crucial role in repairing DNA damage induced by methylating agents like temozolomide and chloroethylating agents such as carmustine, and thereby contributes to chemotherapeutic resistance when these agents are used. This review delves into the structural roles and repair mechanisms of MGMT, with emphasis on th ...[more]

PMID: 38254819

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Project description:Pancreas ductal adenocarcinoma (PDAC) is the third most common cause of cancer death in the USA. While other cancers with historically poor prognoses have benefited from new immunotherapies and targeted agents, the 5-year survival rate for PDAC patients has remained static. The accessibility to genomic testing has improved in recent years, and it is now clear that PDAC is a heterogenous disease, with a subset of patients harboring actionable mutations. There are several targeted therapies approved by the Food and Drug administration (FDA) in PDAC: EGFR inhibitor erlotinib (combined with gemcitabine) in unselected patients, TRK inhibitors larotrectinib and entrectinib for patients with NTRK fusion mutation, the PD-1 inhibitor pembrolizumab for mismatch repair-deficient patients, and the poly-ADP-ribose polymerase (PARP) inhibitor olaparib in patients with germline BRCA mutation as a maintenance therapy. DNA damage repair (DDR) is paramount to genomic integrity and cell survival. The defective repair of DNA damage is one of the hallmarks of cancer, and abnormalities in DDR pathways are closely linked with the development of malignancies and upregulation of these pathways linked with resistance to treatment. The prevalence of somatic and germline mutations in DDR pathways in metastatic PDAC is reported to be approximately 15-25%. Patients with DDR gene alterations benefit from a personalized approach to treatment. Recently, the POLO trial demonstrated a progression-free survival (PFS) benefit in metastatic PDAC patients with a germline BRCA1/2 mutation treated with maintenance olaparib following platinum-based induction chemotherapy. This was the first phase 3 randomized trial to establish a biomarker-driven approach in the treatment of PDAC and establishes a precedent for maintenance therapy in PDAC. The review herein aims to outline the current treatment landscape for PDAC patients with DDR gene-mutated tumors, highlight novel therapeutic approaches focused on surmounting tumor resistance, and explore new strategies which may lead to an expansion in the number of patients who benefit from these targeted treatments.

Dataset Information

The Versatile Attributes of MGMT: Its Repair Mechanism, Crosstalk with Other DNA Repair Pathways, and Its Role in Cancer.

Publications

The Versatile Attributes of MGMT: Its Repair Mechanism, Crosstalk with Other DNA Repair Pathways, and Its Role in Cancer.

Similar Datasets

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