Rationale for a Combination Therapy with the STAT5 Inhibitor AC-4-130 and the MCL1 Inhibitor S63845 in the Treatment of FLT3-Mutated or TET2-Mutated Acute Myeloid Leukemia

被引:9
作者
Seipel, Katja [1 ]
Graber, Carolyn [1 ]
Fluckiger, Laura [1 ]
Bacher, Ulrike [2 ]
Pabst, Thomas [3 ]
机构
[1] Univ Bern, Dept Biomed Res, CH-2008 Bern, Switzerland
[2] Univ Hosp Bern, Dept Hematol, CH-3010 Bern, Switzerland
[3] Univ Hosp Bern, Dept Med Oncol, CH-3010 Bern, Switzerland
基金
瑞士国家科学基金会;
关键词
acute myeloid leukemia (AML); hematological malignancies; FMS-like tyrosine kinase 3 (FLT3); signal transducer and activator of transcription 5 (STAT5); ten-eleven translocation-2 (TET2); tumor suppressor p53 (TP53); myeloid leukemia cell differentiation protein (MCL1); VARIANT ALLELE FREQUENCY; STROMAL CELLS; TET2; EXPRESSION; PHENOTYPE; GENE;
D O I
10.3390/ijms22158092
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in one-third of patients with de novo acute myeloid leukemia (AML). Mutated FLT3 variants are constitutively active kinases signaling via AKT kinase, MAP kinases, and STAT5. FLT3 inhibitors have been approved for the treatment of FLT3-mutated AML. However, treatment response to FLT3 inhibitors may be short-lived, and resistance may emerge. Compounds targeting STAT5 may enhance and prolong effects of FLT3 inhibitors in this subset of patients with FLT3-mutated AML. Here STAT5-inhibitor AC-4-130, FLT3 inhibitor midostaurin (PKC412), BMI-1 inhibitor PTC596, MEK-inhibitor trametinib, MCL1-inhibitor S63845, and BCL-2 inhibitor venetoclax were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells grown in the absence or presence of bone marrow stroma. Synergistic effects on cell viability were detected in both FLT3-mutated and FLT3-wild-type AML cells treated with AC-4-130 in combination with the MCL1 inhibitor S63845. AML patient samples with a strong response to AC-4-130 and S63845 combination treatment were characterized by mutated FLT3 or mutated TET2 genes. Susceptibility of AML cells to AC-4-130, PTC596, trametinib, PKC412, and venetoclax was altered in the presence of HS-5 stroma. Only the MCL1 inhibitor S63845 induced cell death with equal efficacy in the absence or presence of bone marrow stroma. The combination of the STAT5-inhibitor AC-4-130 and the MCL1 inhibitor S63845 may be an effective treatment targeting FLT3-mutated or TET2-mutated AML.
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页数:13
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