Abstract
BackgroundProtein tyrosine phosphatase of regenerating liver 3 (PRL-3) is overexpressed in a subset of AML patients with inferior prognosis, representing an attractive therapeutic target. However, due to relatively shallow pocket of the catalytic site of PRL-3, it is difficult to develop selective small molecule inhibitor.MethodsIn this study, we performed whole-genome lentiviral shRNA library screening to discover synthetic lethal target to PRL-3 in AML. We used specific small molecule inhibitors to validate the synthetic lethality in human PRL-3 high vs PRL-3 low human AML cell lines and primary bone marrow cells from AML patients. AML mouse xenograft model was used to examine the in vivo synergism.ResultsThe list of genes depleted in TF1-hPRL3 cells was particularly enriched for members involved in WNT/β-catenin pathway and AKT/mTOR signaling. These findings prompted us to explore the impact of AKT/mTOR signaling inhibition in PRL-3 high AML cells in combination with WNT/β-catenin inhibitor. VS-5584, a novel, highly selective dual PI3K/mTOR inhibitor, and ICG-001, a WNT inhibitor, were used as a combination therapy. A synthetic lethal interaction between mTOR/AKT pathway inhibition and WNT/β-catenin was validated by a variety of cellular assays. Notably, we found that treatment with these two drugs significantly reduced leukemic burden and prolonged survival of mice transplanted with human PRL-3 high AML cells, but not with PRL-3 low AML cells.ConclusionsIn summary, our results support the existence of cooperative signaling networks between AKT/mTOR and WNT/β-catenin pathways in PRL-3 high AML cells. Simultaneous inhibition of these two pathways could achieve robust clinical efficacy for this subtype of AML patient with high PRL-3 expression and warrant further clinical investigation.
Highlights
Protein tyrosine phosphatase of regenerating liver 3 (PRL-3) is overexpressed in a subset of Acute myeloid leukemia (AML) patients with inferior prognosis, representing an attractive therapeutic target
High expression of PRL-3 is an independent prognostic factor in AML We and others reported that PRL-3 is an independent prognostic factor in AML based on microarray data of human AML [15,16,17,18]
If all AML patients were divided into two groups according to the median expression level of PRL-3 (PRL-3 low: < median level; PRL-3 high: > median level), a significant difference was observed in overall survival between these two groups
Summary
Protein tyrosine phosphatase of regenerating liver 3 (PRL-3) is overexpressed in a subset of AML patients with inferior prognosis, representing an attractive therapeutic target. Acute myeloid leukemia (AML) is a group of heterogeneous diseases, arising from clonal expansion of transformed hematopoietic stem and progenitor cells [1]. Signaling transduction initiated by protein phosphorylation and dephosphorylation governs a host of fundamental cell functions, such as proliferation, growth, survival, and apoptosis [5, 6]. This phospho-switch process is mediated by kinases and phosphatases, respectively. Our group first reported that PRL-3 protein is overexpressed in about half of bone marrow samples of
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