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

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.

Targeting PP2A in cancer: Combination therapies

“…Two papers report on the efficacy of LB100 combination therapy with kinase inhibitors: (1) Sorafenib in the treatment of hepatocellular carcinoma, and (2) Imatinib for BCL-ABL+ leukemia [110, 111]. Fu et al showed that resistance to sorafenib is partially due to a decrease in phosphorylated SMAD3 in hypoxic microenvironments.…”

Rules for PP2A-controlled phosphosignalling and drug responses

“…These novel insights are not only important for general understanding of rules of PP2A-mediated phosphoregulation, but also for realization that all phosphoregulation in cancer cells is not equally susceptible to modulation of PP2A activity. Rather, phosphatase-dominant targets would primarily respond to pharmacological PP2A inhibition 38,60 , whereas various PP2A reactivation therapies 14,15 , would primarily affect kinase-dominant targets.…”

“…The most important notions however might be that different drug classes can be classified based on their PP2A dependency of response, and that directionality rules apply also to PP2A-dependent drug responses. These aspect may become relevant for developing combination strategies with the emerging PP2A-targeted therapies aiming either to re-activate 14,15 , or inhibit 38,60 PP2A.…”

“…Our data also demonstrate how PP2A dephosphorylome activity globally defines drug sensitivities. The insights provided by these results are important for holistic understanding of cell signaling but also may have translational relevance in light of emerging pharmacological approaches for PP2A activity modulation 14,15,38 in human diseases ranging from Alzheimer´s disease to cancer.…”

Inhibition of Protein Phosphatase 2A Sensitizes Mucoepidermoid Carcinoma to Chemotherapy via the PI3K-AKT Pathway in Response to Insulin Stimulus

“…The specificity and kinetics of the PP2A inhibitor LB100 regarding the inhibition of the Ser/Thr phosphatase activity of PP2A were determined in a recent report using the catalytic subunit of recombinant human PP2A and a phosphopeptide (K-R-pT-I-R-R) as a substrate [36]. Compared with multiple kinases, relatively few protein serine/threonine phosphatases (PSPs) control the specific dephosphorylation of thousands of phosphoprotein substrates.…”