title: Effective Concentration of a Multikinase Inhibitor within Bone Marrow Correlates with In Vitro Cell Killing in Therapy-Resistant Chronic Myeloid Leukemia.
abstract: Leukemia cells escape BCR-ABL-targeted therapy by developing mutations, such as T315I, in the p210(BCR-ABL) fusion protein in Philadelphia chromosome-positive chronic myeloid leukemia (CML). Although most effort has been focused on development of new tyrosine kinase inhibitors, enrichment of these small-molecule inhibitors in the tumor tissue can also have a profound impact on treatment outcomes. Here, we report that a 2-hour exposure of the T315I-mutant CML cells to 10 μmol/L of the multikinase inhibitor TG101209 suppressed BCR-ABL-independent signaling and caused cell-cycle arrest at G2-M. Further increase in drug concentration to 17.5 μmol/L blocked phosphorylation of the mutant BCR-ABL kinase and its downstream JAK2 and STAT5. The effective dosage to overcome therapy resistance identified in an in vitro setting serves as a guidance to develop the proper drug formulation for in vivo efficacy. A targeted formulation was developed to achieve sustained bone marrow TG101209 concentration at or above 17.5 μmol/L for effective killing of CML cells in vivo Potent inhibition of leukemia cell growth and extended survival were observed in two murine models of CML treated with 40 mg/kg intravenously administered targeted TG101209, but not with the untargeted drug at the same dosage. Our finding provides a unique approach to develop treatments for therapy-resistant CML. Mol Cancer Ther; 15(5); 899-910. ©2016 AACR.
authors: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas.
authors: Chaofeng
authors: C
authors: Mu
authors: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas.
authors: Xiaoyan
authors: X
authors: Wu
authors: Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors: Helen
authors: H
authors: Ma
authors: Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors: Wenjing
authors: W
authors: Tao
authors: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas.
authors: Guodong
authors: G
authors: Zhang
authors: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas.
authors: Xiaojun
authors: X
authors: Xia
authors: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas.
authors: Jianliang
authors: J
authors: Shen
authors: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas.
authors: Junhua
authors: J
authors: Mai
authors: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas.
authors: Tong
authors: T
authors: Sun
authors: Department of Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors: Xiaoping
authors: X
authors: Sun
authors: Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors: Ralph B
authors: RB
authors: Arlinghaus
authors: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas. Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York. hshen@houstonmethodist.org.
authors: Haifa
authors: H
authors: Shen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D064107:Aurora Kinase B; D016044:Fusion Proteins, bcr-abl; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C522865:TG101209; D000096926:Benzenesulfonamides