The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells

In Ph-positive (Ph(+)) leukemia, the quiescent cell state is one of the reasons for resistance to the BCR-ABL-kinase inhibitor, imatinib. In order to examine the mechanisms of resistance due to quiescence and the effect of the mammalian target of rapamycin inhibitor, everolimus, for such a resistant population, we used Ph(+) acute lymphoblastic leukemia patient cells serially xenotransplanted into NOD/SCID/IL2rγ(null) (NOG) mice. Spleen cells from leukemic mice showed a higher percentage of slow-cycling G(0) cells in the CD34(+)CD38(-) population compared with the CD34(+)CD38(+) and CD34(-) populations. After ex vivo imatinib treatment, more residual cells were observed in the CD34(+)CD38(-) population than in the other populations. Although slow-cycling G(0) cells were insensitive to imatinib in spite of BCR-ABL and CrkL dephosphorylation, combination treatment with everolimus induced substantial cell death, including that of the CD34(+)CD38(-) population, with p70-S6 K dephosphorylation and decrease of MCL-1 expression. The leukemic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse system with the in vivo combination treatment with imatinib and everolimus showed a decrease of tumor burden including CD34(+) cells. These results imply that treatment with everolimus can overcome resistance to imatinib in Ph(+) leukemia due to quiescence.