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

O6-methylguanine-DNA methyltransferase (MGMT) is a critical DNA repair protein that protects the genome by removing mutagenic and cytotoxic adducts from the O6 position of guanine (UniProt P09188). The P140K variant is a specific mutant (Proline to Lysine at position 140) engineered to be resistant to O6-benzylguanine (O6-BG), a small molecule inhibitor used to sensitize tumor cells to chemotherapy (PubMed: 10449305). This variant is primarily utilized in hematopoietic stem cell gene therapy to prevent dose-limiting myelosuppression during aggressive alkylating chemotherapy (PubMed: 12514114). By expressing MGMT(P140K) in bone marrow cells, clinicians can administer higher doses of drugs like temozolomide alongside O6-BG, effectively targeting MGMT-positive tumors while sparing the patient's immune and blood-forming systems. This approach addresses the major clinical challenge of chemotherapy-induced bone marrow toxicity in cancer treatment.

Other names

MGMT P140KO6-alkylguanine-DNA alkyltransferase P140KAGT P140KMethylated-DNA--protein-cysteine methyltransferase P140K

The MGMT P140K variant functions as a suicide DNA repair enzyme that stoichiometrically transfers alkyl groups from the O6 position of guanine to a cysteine residue within its own active site, thereby neutralizing DNA damage caused by alkylating agents (PubMed: 10449305). The P140K mutation specifically alters the active site pocket to prevent the binding and inhibitory action of O6-benzylguanine, while maintaining catalytic activity against smaller alkyl lesions like those produced by temozolomide. In therapeutic applications, this allows for the selective survival of P140K-expressing cells in the presence of both an MGMT inhibitor and an alkylating chemotherapeutic agent.