Selective small molecule inhibitors of p110α and δ isoforms of phosphoinosityl-3-kinase are cytotoxic to human acute myeloid leukemia progenitors

摘要

The phosphoinosityl-3-kinase (PI3K) pathway is frequently constitutively active in blast cells from acute myeloid leukemia (AML) patients. RNA and protein from all four catalytic isoforms of PI3K (p110α, β, γ, and δ) were expressed in 38 AML samples, which also showed expression of phosphorylated Akt Ser473, indicating PI3K activation. Initial treatment of 12 AML samples with inhibitors targeting each of the four isoforms demonstrated that p110α and δ inhibition are more effective in killing AML blast colony-forming cells (CFC) than p110β or γ inhibition. In subsequent experiments, AML CFC from 46 patient samples were treated with the p110α and δ selective inhibitors, PI3Kα inhibitor 2 or PCN5603, and dose-dependent progenitor kill and inhibition of phosphorylated Akt Ser473 expression was observed. AML samples were more sensitive to PI3Kα inhibitor 2 and PCN5603 killing than normal bone marrow or normal peripheral blood CFC (median IC 50 for AML and normal CFCs treated with PI3Kα inhibitor 2, 1.8 and 4.3 μM, respectively, and for PCN5603, 1.9 and 6.2 μM, respectively). Furthermore, treatment of AML cells with PCN5603 also decreased survival of more primitive leukemia progenitors identified in long-term culture (AML long-term culture initiating cells), while less toxicity toward normal bone marrow long-term culture initiating cells was observed. Selective inhibition of the p110α and δ isoforms of PI3K kills AML progenitors while causing relative sparing of analogous normal cells.