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

The O6-methylguanine-DNA methyltransferase P140K mutant (MGMT-P140K) is a genetically engineered variant of the DNA repair enzyme MGMT, which normally removes alkyl groups from the O6 position of guanine in DNA, thereby protecting cells against mutagenic or cytotoxic damage caused by alkylating agents. The P140K mutation, a single amino acid substitution, imparts strong resistance to inactivation by O6-benzylguanine (BG), unlike the wild-type enzyme. This feature enables use of MGMT-P140K in gene therapy to selectively protect transduced hematopoietic progenitor cells from the dose-limiting toxicity of alkylating chemotherapies such as BCNU and temozolomide, while tumor cells remain sensitized. MGMT-P140K has been demonstrated to allow dose-intensified combination therapy and improved survival in animal models, supporting its clinical potential for chemoprotection in cancer treatment[1][2][3][5][6][8].

Other names

O6-methylguanine-DNA methyltransferase P140KP140K MGMTP140K mutant MGMT

Drugs such as BG inhibit wild-type MGMT, increasing tumor cell sensitivity to alkylating chemotherapy. MGMT-P140K mutant confers resistance to BG, allowing protection of gene-modified cells from combined BG/alkylator chemotherapy[2][5][6].