title: Targeting BCL-2 and ABL/LYN in Philadelphia chromosome-positive acute lymphoblastic leukemia.
abstract: Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) remains a challenge. Although the addition of targeted tyrosine kinase inhibitors (TKIs) to standard cytotoxic therapy has greatly improved upfront treatment, treatment-related morbidity and mortality remain high. TKI monotherapy provides only temporary responses and renders patients susceptible to the development of TKI resistance. Thus, identifying agents that could enhance the activity of TKIs is urgently needed. Recently, a selective inhibitor of B cell lymphoma 2 (BCL-2), ABT-199 (venetoclax), has shown impressive activity against hematologic malignancies. We demonstrate that the combination of TKIs with venetoclax is highly synergistic in vitro, decreasing cell viability and inducing apoptosis in Ph(+)ALL. Furthermore, the multikinase inhibitors dasatinib and ponatinib appear to have the added advantage of inducing Lck/Yes novel tyrosine kinase (LYN)-mediated proapoptotic BCL-2-like protein 11 (BIM) expression and inhibiting up-regulation of antiapoptotic myeloid cell leukemia 1 (MCL-1), thereby potentially overcoming the development of venetoclax resistance. Evaluation of the dasatinib-venetoclax combination for the treatment of primary Ph(+)ALL patient samples in xenografted immunodeficient mice confirmed the tolerability of this drug combination and demonstrated its superior antileukemic efficacy compared to either agent alone. These data suggest that the combination of dasatinib and venetoclax has the potential to improve the treatment of Ph(+)ALL and should be further evaluated for patient care.
authors: Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Jessica T
authors: JT
authors: Leonard
authors: Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Joelle S J
authors: JS
authors: Rowley
authors: Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA. Howard Hughes Medical Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Christopher A
authors: CA
authors: Eide
authors: Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR 97239, USA. Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Elie
authors: E
authors: Traer
authors: Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR 97239, USA. Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Brandon
authors: B
authors: Hayes-Lattin
authors: Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA. Department of Pathology, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Marc
authors: M
authors: Loriaux
authors: Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR 97239, USA. Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Stephen E
authors: SE
authors: Spurgeon
authors: Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA. Howard Hughes Medical Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Brian J
authors: BJ
authors: Druker
authors: Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA. Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Jeffrey W
authors: JW
authors: Tyner
authors: Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA. Division of Pediatric Hematology and Oncology, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, OR 97239, USA. changb@ohsu.edu.
authors: Bill H
authors: BH
authors: Chang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D000069439:Dasatinib / Q000008:administration & dosage; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000008:administration & dosage; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage*; D057170:Translational Research, Biomedical; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: C000595707:BCL2 protein, human; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007093:Imidazoles; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011724:Pyridazines; D050799:STAT5 Transcription Factor; D013449:Sulfonamides; C545373:ponatinib; D016315:Proto-Oncogene Proteins c-abl; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C579720:venetoclax; D000069439:Dasatinib