O6-methylguanine-DNA methyltransferase (P140K variant) (MGMT(P140K))

O6-methylguanine-DNA methyltransferase (MGMT) is a critical DNA repair enzyme that protects cells from the cytotoxic effects of alkylating agents by removing adducts from the O6 position of guanine [UniProt: P16455]. The P140K variant is a genetically engineered mutant (Proline to Lysine at position 140) specifically designed for use in hematopoietic stem cell (HSC) gene therapy. This mutation renders the enzyme insensitive to O6-benzylguanine (O6-BG), a potent inhibitor of wild-type MGMT often used to sensitize tumor cells to chemotherapy [Reese et al., 1996; PubMed: 8923031]. By expressing MGMT(P140K) in bone marrow cells, clinicians can administer O6-BG and high-dose alkylating agents like temozolomide to treat systemic or brain cancers while protecting the patient's blood-forming system from dose-limiting myelosuppression [Adair et al., 2012; PubMed: 22553253]. This approach facilitates the selective survival and expansion of gene-modified cells, effectively using the variant as both a chemoprotective agent and a selectable marker for successful engraftment [Zielske et al., 2003; PubMed: 12835663]. The use of MGMT(P140K) is primarily investigated in the treatment of glioblastoma and other high-grade gliomas to allow for more aggressive dosing regimens.

Other names

MGMT P140KO6-alkylguanine-DNA alkyltransferase P140KP140K MGMTO6-methylguanine-DNA methyltransferase P140K

The P140K variant of MGMT is a DNA repair enzyme that removes alkyl groups from the O6 position of guanine via an irreversible, suicide-mechanism transfer to its own internal cysteine residue (Cys145). The specific P140K mutation (Proline to Lysine at position 140) confers resistance to the inhibitor O6-benzylguanine (O6-BG) by altering the active site pocket, preventing O6-BG from binding while preserving the enzyme's ability to repair DNA damaged by alkylating agents like temozolomide [Reese et al., 1996; PubMed: 8923031].