Mechanisms of Pinometostat (EPZ-5676) Treatment-Emergent Resistance in MLL-Rearranged Leukemia
DOT1L is really a protein methyltransferase active in the development and upkeep of MLL-rearranged (MLL-r) leukemia through its ectopic methylation of histones connected with well-characterised leukemic genes. Pinometostat (EPZ-5676), a selective inhibitor of DOT1L, is within clinical rise in relapsed/refractory acute leukemia patients harboring rearrangements from the MLL gene. The observation of responses and subsequent relapses within the adult trial treating MLL-r patients motivated preclinical investigations into potential mechanisms of pinometostat treatment-emergent resistance (TER) in cell lines confirmed to possess MLL-r. TER was achieved in five MLL-r cell lines, KOPN-8, MOLM-13, MV4-11, NOMO-1, and SEM. Two cell lines, KOPN-8 and NOMO-1, were completely characterised to know the mechanisms involved with pinometostat resistance. Unlike a number of other targeted therapies, resistance doesn’t seem to be achieved through drug-caused choice of mutations from the target itself. Rather, we identified both drug efflux transporter dependent and independent mechanisms of potential to deal with pinometostat. In KOPN-8 TER cells, elevated expression from the drug efflux transporter ABCB1 (P-glycoprotein, MDR1) was the main mechanism of drug resistance. In comparison, resistance in NOMO-1 cells occurs via a mechanism apart from upregulation of the specific efflux pump. RNA-seq analysis performed on parental and resistant KOPN-8 and NOMO-1 cell lines supported two unique candidate path mechanisms that could explain the pinometostat resistance noticed in these cell lines. These results are the initial illustration showing TER types of the DOT1L inhibitor pinometostat and could provide helpful tools for investigating clinical resistance.