Abstract
About 25% of patients with acute myeloid leukemia (AML) harbor FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations and their prognosis remains poor. Gilteritinib is a FLT3 inhibitor approved by the US FDA for use in adult FLT3-mutated relapsed or refractory AML patients. Monotherapy, while efficacious, shows short-lived responses, highlighting the need for combination therapies. Here we show that gilteritinib and CUDC-907, a dual inhibitor of PI3K and histone deacetylases, synergistically induce apoptosis in FLT3-ITD AML cell lines and primary patient samples and have striking in vivo efficacy. Upregulation of FLT3 and activation of ERK are mechanisms of resistance to gilteritinib, while activation of JAK2/STAT5 is a mechanism of resistance to CUDC-907. Gilteritinib and CUDC-907 reciprocally overcome these mechanisms of resistance. In addition, the combined treatment results in cooperative downregulation of cellular metabolites and persisting antileukemic effects. CUDC-907 plus gilteritinib shows synergistic antileukemic activity against FLT3-ITD AML in vitro and in vivo, demonstrating strong translational therapeutic potential.
Highlights
Acute myeloid leukemia (AML) is an aggressive, rapidly progressive malignancy
The pancaspase inhibitor Z-VAD-FMK completely abolished caspase 3 cleavage induced by CUDC-907, it was unable to block the downregulation of FMS-like tyrosine kinase 3 (FLT3) caused by the agent (Fig. 1B), demonstrating that FLT3 downregulation was not merely due to caspase activation
Real-time RT-PCR quantification of FLT3 transcripts in MOLM-13 and MV4-11 cell lines, primary patient samples, and MV4-11 murine xenografts post CUDC-907 treatment revealed that CUDC-907 treatment did not reduce FLT3 transcripts, rather a significant increase or no change was detected (Fig. 1E), showing that the reduction of FLT3 protein is through posttranscriptional mechanism
Summary
Acute myeloid leukemia (AML) is an aggressive, rapidly progressive malignancy In adults, it constitutes approximately one-third of all leukemia diagnoses and leukemiarelated deaths[1] and comprises ~1 out of every 5 acute leukemias in children, but over half of the deaths among children with acute leukemia[2]. FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase expressed on the cell surface of early hematopoietic mutations confers an extremely poor prognosis, due to the activation of multiple downstream survival pathways including MAPK/ERK, PI3K/AKT, and JAK/STAT4,5. Activation of AXL, like FLT3, promotes cell survival/growth via enhancement of the activity of its target pathways[6,7], and its expression is inversely correlated with survival and confers a poorer prognosis[8]
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