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      Merit of the paper "PP2A inhibition sensitize cancer stem cells to ABL tyrosine kinase inhibition in BCR-ABL human leukemia" authored by Lai et al. [Science Translational Medicine (2019) Vol. 11, Issue 501, eaau0416, DOI: 10.1126/scitranslmed.aau0416]

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      Protein phosphatase-2A, Tyrosine kinase inhibitors, protein phosphatase inhibitors, BCR-ABL, LB100, Imatinib, CML, ALL
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            Abstract

            The paper by Lai et al. [1] showed that inhibition of PP-2A with LB100 or LB102 in conjunction with Tyrosine kinase Inhibitors (TKIs) was effective at targeting BCR-ABL + blast cells and insensitive leukemic stem cells (LSCs). Perotti et al. [2] has severely criticised the paper by Lai et al [2]. However, Perotti et al. [2] has failed to appreciate an important principle of the role of PP-2A as a tumor suppressor and its regulation in the cell, namely that in general, PP-2A dephosphoryltes and inactivates enzymes and proteins that upregulate cell proliferation, cell survival, tumorigenic and metastasizing pathways but with a limited number of of enzymes and proteins, PP-2A acts to upregulate them. Thus, PP-2A is a double-edge sword and modulation of its activity must be calibrated empirically. Also, Perotti et al. [2] has misunderstood an important principle of enzyme regulation, namely that PP-2A is regulated by inhibitory and activating molecules and not through "targeting proteins" which has not been scientifically verified. It is submitted that the paper by Lai et al. [1] has strong merit as it shows for the first time that an inhibitor of PP-2A can synergize with a TKI.

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            Author and article information

            Journal
            ScienceOpen Preprints
            ScienceOpen
            6 February 2020
            Affiliations
            [1 ] Nachbraht Biomedical Research Institute
            Article
            10.14293/S2199-1006.1.SOR-.PPYEFVR.v1
            c993c520-479b-4343-8363-497a73327436

            This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com .


            The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
            Cell biology,Biochemistry,Molecular medicine,Cancer biology,Life sciences
            Protein phosphatase-2A,Tyrosine kinase inhibitors,protein phosphatase inhibitors,BCR-ABL,LB100,Imatinib,CML,ALL

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