Recent data suggest that the disease-associated microenvironment, known as the leukemic stem cell (LSC) niche, is substantially involved in drug resistance of LSC in BCR-ABL1+ chronic myeloid leukemia (CML). Attacking the LSC niche in CML may thus be an effective approach to overcome drug resistance. We have recently shown that osteoblasts are a major site of niche-mediated LSC resistance against second- and third-generation tyrosine kinase inhibitors (TKI) in CML. In the present study, we screened for drugs that are capable of suppressing the growth and viability of osteoblasts and/or other niche cells and can thereby overcome TKI resistance of CML LSC. Proliferation was analyzed by determining 3H-thymidine uptake in niche-related cells, and apoptosis was measured by Annexin-V/DAPI-staining and flow cytometry. We found that the dual PI3 kinase (PI3K) and mTOR inhibitor BEZ235 and the selective pan-PI3K inhibitor copanlisib suppress proliferation of primary osteoblasts (BEZ235 IC50: 0.05 μM; copanlisib IC50: 0.05 μM), the osteoblast cell line CAL-72 (BEZ235 IC50: 0.5 μM; copanlisib IC50: 1 μM), primary umbilical vein-derived endothelial cells (BEZ235 IC50: 0.5 μM; copanlisib IC50: 0.5 μM), and the vascular endothelial cell line HMEC-1 (BEZ235 IC50: 1 μM; copanlisib IC50: 1 μM), whereas no comparable effects were seen with the mTOR inhibitor rapamycin. Furthermore, we show that BEZ235 and copanlisib cooperate with nilotinib and ponatinib in suppressing proliferation and survival of osteoblasts and endothelial cells. Finally, BEZ235 and copanlisib were found to overcome osteoblast-mediated resistance against nilotinib and ponatinib in K562 cells, KU812 cells and primary CD34+/CD38- CML LSC. Together, targeting osteoblastic niche cells through PI3K inhibition may be a new effective approach to overcome niche-induced TKI resistance in CML. Whether this approach can be translated into clinical application and can counteract drug resistance of LSC in patients with CML remains to be determined in clinical trials.
Keywords: BCR-ABL1 inhibitors; CML; PI3 kinase; drug resistance; leukemic stem cells; mTOR; precision medicine; stem cell niche.
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