Journal
JOURNAL OF HEMATOLOGY & ONCOLOGY
Volume 11, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/s13045-018-0581-9
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Funding
- National Research Foundation Singapore
- Singapore Ministry of Education under its Research Centres of Excellence initiative
- NMRC Clinician-Scientist IRG Grant [CNIG11nov38]
- NMRC Clinician Scientist Investigator award
- RNA Biology Center at CSI Singapore, NUS, from the Singapore Ministry of Education's Tier 3 grants [MOE2014-T3-1-006]
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Background: 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. However, due to relatively shallow pocket of the catalytic site of PRL-3, it is difficult to develop selective small molecule inhibitor. Methods: In 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. Results: The list of genes depleted in TF1-hPRL3 cells was particularly enriched for members involved in WNT/beta-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/beta-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/beta-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. Conclusions: In summary, our results support the existence of cooperative signaling networks between AKT/mTOR and WNT/beta-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.
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