Mechanisms of action and resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (As₂O₃) in acute promyelocytic leukemia

Since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (As₂O₃) for the treatment of acute promyelocytic leukemia (APL), the overall survival rate has improved dramatically. However, relapse/refractory patients showing resistance to ATRA and/or As₂O₃ are recognized as a clinically significant problem. Genetic mutations resulting in amino acid substitution in the retinoic acid receptor alpha (RARα) ligand binding domain (LBD) and the PML-B2 domain of PML-RARα, respectively, have been reported as molecular mechanisms underlying resistance to ATRA and As₂O₃. In the LBD mutation, ATRA binding with LBD is generally impaired, and ligand-dependent co-repressor dissociation and degradation of PML-RARα by the proteasome pathway, leading to cell differentiation, are inhibited. The PML-B2 mutation interferes with the direct binding of As₂O₃ with PML-B2, and PML-RARα SUMOylation with As₂O₃ followed by multimerization and degradation is impaired. To overcome ATRA resistance, utilization of As₂O₃ provides a preferable outcome, and recently, a synthetic retinoid Am80, which has a higher binding affinity with PML-RARα than ATRA, has been tested in the clinical setting. However, no strategy attempted to date has been successful in overcoming As₂O₃ resistance. Detailed genomic analyses using patient samples harvested repeatedly may help in predicting the prognosis, selecting the effective targeting drugs, and designing new sophisticated strategies for the treatment of APL.