Inhibition of Mcl-1 Synergistically Enhances the Antileukemic Activity of Gilteritinib and MRX-2843 in Preclinical Models of <i>FLT3</i>-Mutated Acute Myeloid Leukemia
Shuangshuang Wu,
Holly Edwards,
Deying Wang,
Shuang Liu,
Xinan Qiao,
Jenna Carter,
Yue Wang,
Jeffrey W. Taub,
Guan Wang,
Yubin Ge
Affiliations
Shuangshuang Wu
Department of Pediatric Hematology, The First Hospital of Jilin University, Changchun 130021, China
Holly Edwards
Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48202, USA
Deying Wang
The Tumor Center of the First Hospital of Jilin University, Changchun 130021, China
Shuang Liu
National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China
Xinan Qiao
National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China
Jenna Carter
Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI 48201, USA
Yue Wang
Department of Pediatric Hematology, The First Hospital of Jilin University, Changchun 130021, China
Jeffrey W. Taub
Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI 48202, USA
Guan Wang
National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China
Yubin Ge
Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48202, USA
FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (FLT3-ITD) mutations occur in about 25% of all acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3 inhibitors have been developed to treat patients with FLT3-mutated AML and have shown promise, though the acquisition of resistance occurs, highlighting the need for combination therapies to prolong the response to FLT3 inhibitors. In this study, we investigated the selective Mcl-1 inhibitor AZD5991 in combination with the FLT3 inhibitors gilteritinib and MRX-2843. The combinations synergistically induce apoptosis in AML cell lines and primary patient samples. The FLT3 inhibitors downregulate c-Myc transcripts through the suppression of the MEK/ERK and JAK2/STAT5 pathways, resulting in the decrease in c-Myc protein. This suppression of c-Myc plays an important role in the antileukemic activity of AZD5991. Interestingly, the suppression of c-Myc enhances AZD5991-inudced cytochrome c release and the subsequent induction of apoptosis. AZD5991 enhances the antileukemic activity of the FLT3 inhibitors gilteritinib and MRX-2843 against FLT3-mutated AML in vitro, warranting further development.
