Targeting BCL-2 and ABL/LYN in Philadelphia chromosome-positive acute lymphoblastic leukemia

Jessica T. Leonard, Joelle S J Rowley, Christopher A. Eide, Elie Traer, Brandon Hayes-Lattin, Marc Loriaux, Stephen Spurgeon, Brian Druker, Jeffrey Tyner, Bill Chang

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 hematologicmalignancies. 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 immunodeficientmice 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.

Original languageEnglish (US)
Article number354ra114
JournalScience Translational Medicine
Volume8
Issue number354
DOIs
StatePublished - Aug 31 2016

Fingerprint

Philadelphia Chromosome
B-Cell Lymphoma
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Protein-Tyrosine Kinases
Therapeutics
Myeloid Leukemia
Myeloid Cells
Drug Combinations
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide
Cell Survival
Patient Care
Up-Regulation
Apoptosis
Morbidity
Mortality
Dasatinib

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Targeting BCL-2 and ABL/LYN in Philadelphia chromosome-positive acute lymphoblastic leukemia. / Leonard, Jessica T.; Rowley, Joelle S J; Eide, Christopher A.; Traer, Elie; Hayes-Lattin, Brandon; Loriaux, Marc; Spurgeon, Stephen; Druker, Brian; Tyner, Jeffrey; Chang, Bill.

In: Science Translational Medicine, Vol. 8, No. 354, 354ra114, 31.08.2016.

Research output: Contribution to journalArticle

@article{b1444fcdeebb46b493d73f80b271a9f6,
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 hematologicmalignancies. 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 immunodeficientmice 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.",
author = "Leonard, {Jessica T.} and Rowley, {Joelle S J} and Eide, {Christopher A.} and Elie Traer and Brandon Hayes-Lattin and Marc Loriaux and Stephen Spurgeon and Brian Druker and Jeffrey Tyner and Bill Chang",
year = "2016",
month = "8",
day = "31",
doi = "10.1126/scitranslmed.aaf5309",
language = "English (US)",
volume = "8",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "354",

}

TY - JOUR

T1 - Targeting BCL-2 and ABL/LYN in Philadelphia chromosome-positive acute lymphoblastic leukemia

AU - Leonard, Jessica T.

AU - Rowley, Joelle S J

AU - Eide, Christopher A.

AU - Traer, Elie

AU - Hayes-Lattin, Brandon

AU - Loriaux, Marc

AU - Spurgeon, Stephen

AU - Druker, Brian

AU - Tyner, Jeffrey

AU - Chang, Bill

PY - 2016/8/31

Y1 - 2016/8/31

N2 - 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 hematologicmalignancies. 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 immunodeficientmice 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.

AB - 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 hematologicmalignancies. 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 immunodeficientmice 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.

UR - http://www.scopus.com/inward/record.url?scp=84988908564&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84988908564&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.aaf5309

DO - 10.1126/scitranslmed.aaf5309

M3 - Article

C2 - 27582059

AN - SCOPUS:84988908564

VL - 8

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 354

M1 - 354ra114

ER -