Inhibition of O6‐methylguanine‐DNA‐methyltransferase (MGMT) by lomeguatrib reduces multiple myeloma cell viability and impairs DNA repair in MGMT‐proficient cells

The function of direct DNA damage repair protein, namely MGMT in MM, and the impact of MGMT on melphalan treatment remains unclear. We showed a significantly higher MGMT mRNA expression in CD138+ myeloma cells than in matched CD138‐nontumorigenic cells derived from newly diagnosed and relapsed/refractory MM patients using qPCR. However, using gene expression databases, a similar expression of MGMT was observed during disease progression. MGMT depletion by its specific inhibitor lomeguatrib reduced myeloma cell viability, impaired S phase entry and DNA repair, and increased DNA damage and apoptosis. Apoptosis and DNA damage were further elevated by combined treatment with lomeguatrib and melphalan in RPMI 8226 cells. This is the first study demonstrating MGMT inhibition enhances DNA damage‐induced apoptosis and melphalan cytotoxicity in MGMT‐proficient MM cells and suggesting using lomeguatrib might have clinical importance in treating MM and overcoming melphalan resistance in MGMT‐proficient patients. MGMT mRNA expression was significantly increased in CD138+ myeloma cells compared with their matched CD138‐nontumorigenic cells and inhibition of MGMT by its specific inhibitor lomeguatrib in MM cells reduced DNA repair, cell viability, and S phase entry and increased DNA damage and apoptosis. Apoptosis and DNA damage were further elevated in melphalan‐treated RPMI 8226 cells, where MGMT expression is absent.