Open AccessVenetoclax enhances DNA damage induced by XPO1 inhibitors: A novel mechanism underlying the synergistic antileukaemic effect in acute myeloid leukaemia
Author(s) -
Yu Hanxi,
Wu Shuangshuang,
Liu Shuang,
Li Xinyu,
Gai Yuqing,
Lin Hai,
Wang Yue,
Edwards Holly,
Ge Yubin,
Wang Guan
Publication year - 2022
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.17274
Subject(s) - venetoclax , myeloid leukemia , dna damage , cancer research , dna repair , downregulation and upregulation , mechanism of action , chemistry , dna , pharmacology , leukemia , medicine , gene , biochemistry , chronic lymphocytic leukemia , in vitro
Acute myeloid leukaemia (AML) is a highly heterogeneous haematologic malignancy with poor prognosis. We previously showed synergistic antileukaemic interaction between exportin 1 (XPO1) inhibitor KPT‐330 (Selinexor) and Bcl‐2 inhibitor venetoclax (ABT‐199) in preclinical models of AML, which was partially meditated by Mcl‐1, although the full mechanism of action remains unknown. In this study, using real‐time RT‐PCR and Western blot analysis, we show that inhibition of XPO1 via KPT‐330 or KPT‐8602 (Eltanexor) decreases the mRNA and protein levels of c‐Myc, CHK1, WEE1, RAD51 and RRM2. KPT‐330 and KPT‐8602 induce DNA damage, as determined by alkaline comet assay. In addition, we demonstrate that venetoclax enhances KPT‐330‐ and KPT‐8602‐induced DNA damage, likely through inhibition of DNA damage repair. This study provides new insight into the molecular mechanism underlying the synergistic antileukaemic activity between venetoclax and XPO1 inhibitors against AML. Our data support the clinical evaluation of this promising combination therapy for the treatment of AML.