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PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL+ human leukemia

Posted February 8, 2018 | Publications

Lai D, Chen M, Su J, Liu X, Rothe K, Hu K, Forrest DL, Eaves CJ, Morin GB & Jiang X. PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL+ human leukemia. Sci Transl Med 10: 427, 2018.

This article was highlighted in the journal’s press package, informally known as the MedPak on Sunday, 4 February, 2018, and an article of this work was featured on Science in the City on Feb 26, 2018. 

Abstract
Overcoming drug resistance and targeting leukemic stem cells (LSCs) remain major challenges in curing BCR-ABL+ human leukemia. Using an advanced drug/proliferation screen, we have uncovered a prosurvival role for protein phosphatase 2A (PP2A) in tyrosine kinase inhibitor (TKI)-insensitive leukemic cells, regulated by an Abelson helper integration site-1-mediated PP2A-β-catenin-BCR-ABL-JAK2 protein complex. Genetic and pharmacological inhibition of PP2A impairs survival of TKI nonresponder cells and sensitizes them to TKIs in vitro, inducing a dramatic loss of several key proteins, including β-catenin. We also demonstrate that the clinically validated PP2A inhibitors LB100 and LB102, in combination with TKIs, selectively eliminate treatment-naïve TKI-insensitive stem and progenitor cells, while sparing healthy counterparts. In addition, PP2A inhibitors and TKIs act synergistically to inhibit the growth of TKI-insensitive cells, as assessed by combination index analysis. The combination eliminates infiltrated BCR-ABL+ blast cells and drug-insensitive LSCs and confers a survival advantage in preclinical xenotransplant models. Thus, dual PP2A and BCR-ABL inhibition may be a valuable therapeutic strategy to synergistically target drug-insensitive LSCs that maintain minimal residual disease in patients.
PMID: 29437150