pf-477736 and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Interactions between the dual BCR/ABL and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in BCR/ABL(+) leukemia cells, particularly imatinib-resistant cells, including those with the T315I mutation. Bosutinib blocked PF-00477736-induced ERK1/2 activation and sharply increased apoptosis in association with Mcl-1 inhibition, p34(cdc2) dephosphorylation, BimEL up-regulation, and DNA damage in imatinib-resistant CML or Ph(+) ALL cell lines. Inhibition of Src or MEK1 by shRNA significantly enhanced PF-0047736 lethality. Bosutinib/PF-00477736 co-treatment also potentiated cell death in CD34(+) CML patient samples, including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations, but was minimally toxic to normal CD34(+) cells. Finally, combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model. Together, these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph(+) ALL.

Topics: Amino Acid Substitution; Aniline Compounds; Animals; Antineoplastic Agents; Benzamides; Benzodiazepinones; Checkpoint Kinase 1; Drug Resistance, Neoplasm; Drug Synergism; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; K562 Cells; Leukemia, Lymphocytic, Chronic, B-Cell; MAP Kinase Kinase 1; MAP Kinase Signaling System; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mutation, Missense; Myeloid Cell Leukemia Sequence 1 Protein; Nitriles; Piperazines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Protein Kinases; Pyrazoles; Pyrimidines; Quinolines; Xenograft Model Antitumor Assays