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Sci Transl Med. 2018 Feb 7;10(427). pii: eaan8735. doi: 10.1126/scitranslmed.aan8735.

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

Lai D1,2, Chen M1, Su J1,3, Liu X1,2, Rothe K1,3, Hu K1, Forrest DL2,4, Eaves CJ1,2,3, Morin GB3,5, Jiang X6,2,3.

Author information

1
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
2
Department of Medicine, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada.
3
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada.
4
Leukemia/Bone Marrow Transplant Program of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada.
5
Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
6
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada. xjiang@bccrc.ca.

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.

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