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.

Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies

“…These combinations appear to be effective across a broad percentage of AML patient samples, irrespective of cohort subtype heterogeneity. Consistent with these observations, recent reports indicate the combined inhibition of BCR-ABL1 and BCL2 is a promising strategy for targeting Philadelphia chromosomepositive ALL as well as the stem cell population in chronic myeloid leukemia (32,33). We also observed certain combinations with venetoclax to be effective on CLL samples with 13q deletions.…”

Pathways and mechanisms of venetoclax resistance

“…[86] The combination of BCR-ABL tyrosine kinase inhibitors (TKIs) and venetoclax is highly synergistic in vitro against Philadelphia chromosome positive (Ph + ) ALL. [87] Furthermore, dasatinib and ponatinib, through their effects on the Lck/Yes novel (LYN) tyrosine kinase, may induce BIM and inhibit up-regulation of MCL-1, thus potentially circumventing the development of venetoclax resistance. [87] The dasatinib/venetoclax combination was synergistic against patient-derived Ph + ALL samples and in xenograft models in mice, arguing for a clinical trial of this regimen in Ph + ALL.…”

“…[87] The dasatinib/venetoclax combination was synergistic against patient-derived Ph + ALL samples and in xenograft models in mice, arguing for a clinical trial of this regimen in Ph + ALL. [87]…”

How I treat Philadelphia chromosome–positive acute lymphoblastic leukemia

“…Other methods of enhancing the activity of TKIs such as combination with the BCL-2 inhibitor venetoclax have been demonstrated in preclinical studies and may provide a promising approach to be investigated in future trials. 56 The availability of more effective agents both in the frontline and relapse settings is providing a range of possibilities for treating this disease that may allow individualized therapy based on patient characteristics, donor availability (including novel donor sources such as haplo-identical donors), and MRD clearance.…”