Research ArticleCancer

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

Science Translational Medicine  31 Aug 2016:
Vol. 8, Issue 354, pp. 354ra114
DOI: 10.1126/scitranslmed.aaf5309

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Showing ALL that resistance is futile

Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) carries the BCR-ABL translocation; however, despite the existence of drugs that target this translocation, Ph+ALL remains very difficult to treat, and single-drug treatment is usually ineffective. Leonard et al. showed that venetoclax, an apoptosis-promoting drug, is effective in treating this disease and that dasatinib, an inhibitor of BCR-ABL, blocks a common mechanism of resistance to venetoclax. As a result, these two drugs work together synergistically in vitro and in preclinical models, offering a promising approach toward the rational treatment of this disease.

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.

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