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.

Abstract

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.

• Authors: Katja Seipel, Carolyn Graber, Laura Flückiger, Ulrike Bacher, Thomas Pabst
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 15 (Jul 28 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34360855 (Publication Type: Journal Article)

Chemical References

• DNA-Binding Proteins
• Proto-Oncogene Proteins
• Pyrimidines
• S63845
• STAT5 Transcription Factor
• STAT5A protein, human
• Thiophenes
• Tumor Suppressor Proteins
• Dioxygenases
• TET2 protein, human
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Cell Line, Tumor
• DNA-Binding Proteins (genetics)
• Dioxygenases
• Humans
• Leukemia, Myeloid, Acute (drug therapy)
• Proto-Oncogene Proteins (genetics)
• Pyrimidines (therapeutic use)
• STAT5 Transcription Factor (antagonists & inhibitors)
• Thiophenes (therapeutic use)
• Tumor Suppressor Proteins (antagonists & inhibitors)
• fms-Like Tyrosine Kinase 3 (genetics)