All-Trans Retinoic Acid Synergizes with Enasidenib to Induce Differentiation of IDH2-Mutant Acute Myeloid Leukemia Cells.
Yonsei Med J
; 61(9): 762-773, 2020 Sep.
Article
em En
| MEDLINE
| ID: mdl-32882760
ABSTRACT
PURPOSE:
Pharmacological inhibition of mutant isocitrate dehydrogenase (IDH) reduces R-2-hydroxyglutarate (2-HG) levels and restores cellular differentiation in vivo and in vitro. The IDH2 inhibitor enasidenib (AG-221) has been approved by the FDA as a first-in-class inhibitor for the treatment of relapsed or refractory (R/R) IDH2-mutant acute myeloid leukemia (AML). In this study, the effects of a combination of all-trans retinoic acid (ATRA) and AG-221 on AML cell differentiation was explored, along with the mechanisms employed by IDH2-mutant cells in AML. MATERIALS ANDMETHODS:
We treated the human AML cell line, IDH2-mutant-TF-1, and primary human AML cells carrying IDH2 mutation with 30 µM AG-221 and 100 nM ATRA, alone or in combination.RESULTS:
Combined treatment with AG-221 and ATRA inhibited 2-HG production and resulted in synergistic effects on differentiation among IDH2-mutant AML cells and primary AML cells expressing IDH2 mutation. Combined treatment with AG-221 and ATRA altered autophagic activity. AG-221 and ATRA treatment-induced differentiation of IDH2-mutant AML cells was associated with autophagy induction, without suppressing autophagy flux at maturation and degradation stages. A RAF-1/MEK/ERK pathway was founded to be associated with AG-221 and ATRA-induced differentiation in IDH2-mutant AML cells. IDH-associated changes in histone methylation markers decreased after AG-221 and ATRA combination treatment.CONCLUSION:
Our preliminary evidence indicates that the addition of ATRA to treatments with IDH2 inhibitor may lead to further improvements or increases in response rates in IDH2-mutant AML patients who do not appear to benefit from treatments with IDH2 inhibitor alone.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tretinoína
/
Triazinas
/
Leucemia Mieloide Aguda
/
Diferenciação Celular
/
Resistencia a Medicamentos Antineoplásicos
/
Inibidores Enzimáticos
/
Aminopiridinas
/
Isocitrato Desidrogenase
/
Antineoplásicos
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article