PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL+ human leukemia
Menée in vitro et à l'aide d'un modèle murin transgénique, cette étude montre que l'inhibition de la phosphatase PP2A sensibilise aux inhibiteurs de tyrosine kinase ABL les cellules souches de leucémie humaine exprimant la protéine de fusion BCR-ABL
Imatinib, the classic targeted drug for the treatment of cancer, was designed to target the BCR-ABL fusion protein in chronic myeloid leukemia and has saved many patients’ lives. Unfortunately, some leukemias are resistant to imatinib despite having the BCR-ABL translocation, and others can develop resistance during treatment. Moreover, imatinib generally does not eradicate the leukemic stem cells and therefore requires continued treatment to maintain efficacy, so combination approaches are still needed. Lai et al. discovered that protein phosphatase 2A is a therapeutic target in imatinib-insensitive leukemia cells, including stem cells, and that the combination of imatinib and related drugs with PP2A inhibition effectively kills these cancer cells.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.