Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL+ leukemia cells

• Published in: Leukemia research Vol. 39; no. 1; pp. 65 - 71
• Main Authors: Nguyen, Tri, Hawkins, Elisa, Kolluri, Akhil, Kmieciak, Maciej, Park, Haeseong, Lin, Hui, Grant, Steven
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2015
• Subjects: Amino Acid Substitution; Aniline Compounds - agonists; Aniline Compounds - pharmacology; Animals; Antineoplastic Agents - pharmacology; BCR/ABL; Benzamides; Benzodiazepinones - agonists; Benzodiazepinones - pharmacology; Bosutinib; Checkpoint Kinase 1; Chk1 inhibitor; Chronic myeloid leukemia; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Drug Synergism; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Hematology, Oncology and Palliative Medicine; Humans; Imatinib Mesylate; K562 Cells; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; MAP Kinase Kinase 1 - genetics; MAP Kinase Kinase 1 - metabolism; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - genetics; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Mutation, Missense; Myeloid Cell Leukemia Sequence 1 Protein; Nitriles - agonists; Nitriles - pharmacology; Piperazines; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protein Kinase Inhibitors; Protein Kinases - metabolism; Pyrazoles - agonists; Pyrazoles - pharmacology; Pyrimidines; Quinolines - agonists; Quinolines - pharmacology; Xenograft Model Antitumor Assays; mitogen-activated protein kinase; ALL; MEK; CML; BCR/ABL; acute lymphoblastic leukemia; chronic myeloid leukemia; extracellular-signal-regulated kinases; Chk1 inhibitor; Bosutinib; ERK; Chronic myeloid leukemia
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/j.leukres.2014.10.009

Highlights • Bosutinib/PF co-treatment synergically induces apoptosis in imatinib-resistant cells. • Bosutinib blocks PF-induced ERK1/2 activation and sharply increases apoptosis. • Bosutinib/PF suppresses BaF3/T315I tumor growth and prolongs survival. • Bosutinib/PF potentiates apoptosis in CML patient samples but not normal cells.