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Title: A loss-of-function genetic screening reveals synergistic targeting of AKT/mTOR and WTN/β-catenin pathways for treatment of AML with high PRL-3 phosphatase
Authors: Zhou, J 
Toh, S.H.-M
Chan, Z.-L
Quah, J.Y
Chooi, J.-Y 
Tan, T.Z 
Chong, P.S.Y 
Zeng, Q 
Chng, W.-J 
Keywords: beta catenin
mammalian target of rapamycin
PRL 3 phosphatase
protein kinase B
short hairpin RNA
unclassified drug
Wnt protein
beta catenin
MTOR protein, human
protein kinase B
protein tyrosine phosphatase
PTP4A3 protein, human
target of rapamycin kinase
tumor protein
acute myeloid leukemia
acute myeloid leukemia cell line
Akt/mTOR signaling
animal experiment
animal model
bone marrow cell
cancer prognosis
cancer survival
cell assay
controlled study
enzyme inhibition
gene library
genetic screening
human cell
in vitro study
in vivo study
protein expression
protein protein interaction
protein targeting
Wnt beta catenin signaling
Wnt signaling
acute myeloid leukemia
genetic screening
nonobese diabetic mouse
SCID mouse
Wnt signaling
beta Catenin
Genetic Testing
Leukemia, Myeloid, Acute
Mice, Inbred NOD
Mice, SCID
Neoplasm Proteins
Protein Tyrosine Phosphatases
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
Wnt Signaling Pathway
Issue Date: 2018
Citation: Zhou, J, Toh, S.H.-M, Chan, Z.-L, Quah, J.Y, Chooi, J.-Y, Tan, T.Z, Chong, P.S.Y, Zeng, Q, Chng, W.-J (2018). A loss-of-function genetic screening reveals synergistic targeting of AKT/mTOR and WTN/β-catenin pathways for treatment of AML with high PRL-3 phosphatase. Journal of Hematology and Oncology 11 (1) : 36. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: 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/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. Conclusions: In 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. © 2018 The Author(s).
Source Title: Journal of Hematology and Oncology
ISSN: 17568722
DOI: 10.1186/s13045-018-0581-9
Rights: Attribution 4.0 International
Appears in Collections:Staff Publications

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