Dual targeting of the ABL and LYN kinases and BCL2 synergizes to promote Ph+ALL cell apoptosis.
Major finding: Dual targeting of the ABL and LYN kinases and BCL2 synergizes to promote Ph+ALL cell apoptosis.
Mechanism: LYN inhibition upregulates BIM and downregulates MCL1 to potentiate BCL2 inhibition.
Impact: Combined treatment with multikinase inhibitors and venetoclax may be effective in patients with Ph+ALL.
Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) is an aggressive subtype characterized by the BCR–ABL translocation. Targeted therapy against the ABL kinase with tyrosine kinase inhibitors (TKI) achieves short-term responses, but resistance often develops, in part through upregulation of BCL2 family antiapoptotic proteins. The BCL2 inhibitor venetoclax is effective in multiple hematologic malignancies, prompting Leonard and colleagues to investigate its use in Ph+ALL. A Ph+ALL cell line and two patient samples showed sensitivity to venetoclax plus dasatinib; these cells exhibited a high ratio of BCL2 to MCL1, an antiapoptotic protein not inhibited by venetoclax, compared with insensitive cells. Further, venetoclax synergized BCR–ABL TKIs to enhance apoptosis of Ph+ALL cells. The highest degree of synergy was observed with the multikinase inhibitors ponatinib and dasatinib, both of which induced expression of the proapoptotic protein BIM. Ponatinib and dasatinib inhibit multiple kinases in addition to ABL, including LYN, and knockdown of ABL or LYN had similar effects to the inhibitors and resulted in enhanced apoptosis and synergy with venetoclax, suggesting that multikinase inhibitors synergize with venetoclax by suppressing both ABL and LYN. Combined treatment with venetoclax and dasatinib was well tolerated in a mouse model of Ph+ALL and reduced the disease burden more effectively than either single agent. Moreover, resistance to venetoclax, which can occur via upregulation of MCL1, was prevented by dasatinib and ponatinib, which blocked LYN activity to reduce STAT5 phosphorylation and prevent MCL1 upregulation, indicating that inhibitors that target both ABL and LYN may prevent venetoclax resistance in Ph+ALL. The finding that inhibition of BCL2 and ABL/LYN synergize to promote Ph+ALL cell apoptosis and prevent resistance to venetoclax provides a rationale for further clinical investigation of this drug combination in this disease.
Leonard JT, Rowley JS, Eide CA, Traer E, Hayes-Lattin B, Loriaux M, et al. Targeting BCL-2 and ABL/LYN in Philadelphia chromosome–positive acute lymphoblastic leukemia. Sci Transl Med 2016;8:354ra114.
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