Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice.
Antineoplastic-Agents, B-Lymphocytes, Blast-Crisis, Cell-Line-Tumor, Cell-Transformation-Neoplastic, Fusion-Proteins-bcr-abl, Humans, Leukemia-B-Cell-Acute, Leukemia-Myeloid-Philadelphia-Positive, Mice-Inbred-BALB-C, Mice-Inbred-C57BL, Mice-Knockout, Piperazines, Protein-Kinase-Inhibitors, Pyrimidines, Thiazoles, Tumor-Stem-Cells, src-Family-Kinases
Proc Natl Acad Sci U S A 2006 Nov; 103(45):16870-5.
It is generally believed that shutting down the kinase activity of BCR-ABL by imatinib will completely inhibit its functions, leading to inactivation of its downstream signaling pathways and cure of the disease. Imatinib is highly effective at treating human Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) in chronic phase but not Ph(+) B cell acute lymphoblastic leukemia (B-ALL) and CML blast crisis. We find that SRC kinases activated by BCR-ABL remain fully active in imatinib-treated mouse leukemic cells, suggesting that imatinib does not inactivate all BCR-ABL-activated signaling pathways. This SRC pathway is essential for leukemic cells to survive imatinib treatment and for CML transition to lymphoid blast crisis. Inhibition of both SRC and BCR-ABL kinase activities by dasatinib affords complete B-ALL remission. However, curing B-ALL and CML mice requires killing leukemic stem cells insensitive to both imatinib and dasatinib. Besides BCR-ABL and SRC kinases, stem cell pathways must be targeted for curative therapy of Ph(+) leukemia.
Hu, Y; Swerdlow, S; Duffy, T M.; Weinmann, R; Lee, F Y.; and Li, S, "Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice." (2006). Faculty Research 2000 - 2009. 1412.