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
The FMS-like tyrosine kinase 3 (<i>FLT3</i>) 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...
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MDPI AG
2021-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/15/8092 |
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| author | Katja Seipel Carolyn Graber Laura Flückiger Ulrike Bacher Thomas Pabst |
| author_facet | Katja Seipel Carolyn Graber Laura Flückiger Ulrike Bacher Thomas Pabst |
| author_sort | Katja Seipel |
| collection | DOAJ |
| description | The FMS-like tyrosine kinase 3 (<i>FLT3</i>) 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 <i>FLT3</i>-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 <i>FLT3</i>-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 <i>FLT3</i>-mutated and <i>FLT3</i>-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 <i>FLT3</i> or mutated <i>TET2</i> 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 <i>FLT3</i>-mutated or <i>TET2</i>-mutated AML. |
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| language | English |
| last_indexed | 2024-03-10T09:15:32Z |
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| spelling | doaj.art-ff886233691a4f84b5ec6e1f505e10272023-11-22T05:43:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-07-012215809210.3390/ijms22158092Rationale 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 LeukemiaKatja Seipel0Carolyn Graber1Laura Flückiger2Ulrike Bacher3Thomas Pabst4Department for Biomedical Research, University of Bern, 2008 Bern, SwitzerlandDepartment for Biomedical Research, University of Bern, 2008 Bern, SwitzerlandDepartment for Biomedical Research, University of Bern, 2008 Bern, SwitzerlandDepartment of Hematology, University Hospital Bern, 3010 Bern, SwitzerlandDepartment of Medical Oncology, University Hospital Bern, 3010 Bern, SwitzerlandThe FMS-like tyrosine kinase 3 (<i>FLT3</i>) 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 <i>FLT3</i>-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 <i>FLT3</i>-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 <i>FLT3</i>-mutated and <i>FLT3</i>-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 <i>FLT3</i> or mutated <i>TET2</i> 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 <i>FLT3</i>-mutated or <i>TET2</i>-mutated AML.https://www.mdpi.com/1422-0067/22/15/8092acute myeloid leukemia (AML)hematological malignanciesFMS-like tyrosine kinase 3 (FLT3)signal transducer and activator of transcription 5 (STAT5)ten-eleven translocation-2 (TET2)tumor suppressor p53 (TP53) |
| spellingShingle | Katja Seipel Carolyn Graber Laura Flückiger Ulrike Bacher Thomas Pabst 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 International Journal of Molecular Sciences 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) |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | 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) |
| url | https://www.mdpi.com/1422-0067/22/15/8092 |
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