Malignant transformation and clonal expansion require acquisition of both proliferative and survival advantages relative to normal cells. The BCL-2 family is composed of both pro-apoptotic and anti-apoptotic proteins, and aberrant expression of anti-apoptotic family members underlies the survival advantage in several types of B-cell lymphoproliferative disorders. Programmed cell death is a consequence of mitochondrial disruption induced by the pro-apoptotic proteins BCL-2-associated-X-protein (BAX) and BCL-2 homologous antagonist killer (BAK).1 Apoptosis is inhibited by the binding of BCL-2 (and related proteins including B-cell lymphoma extra large [BCL-XL] to the BH3 domain of BAX and BAK. The importance of anti-apoptosis in the pathobiology of lymphoma is underscored by the consequence of the t(14;18) translocation that is present in the majority of follicular lymphomas and also occurs in up to 30 percent of diffuse large cell lymphoma. In this case, the translocation brings BCL-2 under the control of the immunoglobulin heavy-chain gene enhancer, resulting in constitutive expression of BCL-2. Aberrant expression of BCL-2 is also observed in mantle cell lymphoma and in acute and chronic leukemias and is one of the two genes (along with myc) that is overexpressed in the markedly aggressive “double-hit” lymphomas. Because of the important role that it plays in the pathophysiology of B-cell lymphoproliferative disorders, BCL-2 is a tantalizing therapeutic target. ABT-263 (navitoclax) was developed as an inhibitor of BCL-2, but its clinical utility has been compromised by dose-limiting thrombocytopenia. The problem is that, in addition to inhibiting BCL-2, ABT-263 binds with high affinity to BCL-XL, the anti-apoptotic protein that is critical for platelet survival.
ABT-199 Selectively Kills BCL-2-Dependent Tumor Cells While Sparing Platelets. A) Navitoclax (ABT-263) binds to both BCL-2 and BCL-XL. Platelets are dependent on the anti-apoptotic activity of BCL-XL for survival. Consequently, thrombocytopenia is a dose-limiting adverse effect of treatment with navitoclax. B) ABT-199 is specific for BCL-2 and induces selective death of BCL-2-dependent tumor cells while sparing platelets.Reprinted from Cancer Cell, 23, Davids MS and Letai A, Taking Dead Aim at BCL-2, page 140, 2013, with permission from Elsevier. Figure created by Richard Oakley.
ABT-199 Selectively Kills BCL-2-Dependent Tumor Cells While Sparing Platelets. A) Navitoclax (ABT-263) binds to both BCL-2 and BCL-XL. Platelets are dependent on the anti-apoptotic activity of BCL-XL for survival. Consequently, thrombocytopenia is a dose-limiting adverse effect of treatment with navitoclax. B) ABT-199 is specific for BCL-2 and induces selective death of BCL-2-dependent tumor cells while sparing platelets.Reprinted from Cancer Cell, 23, Davids MS and Letai A, Taking Dead Aim at BCL-2, page 140, 2013, with permission from Elsevier. Figure created by Richard Oakley.
Souers and colleagues utilized structure-based drug design with guidance provided by x-ray crystallography to develop a more selective BCL-2 inhibitor, ABT-199, through successive modifications of ABT-263. ABT-199 has potent activity against BCL-2 while sparing BCL-XL, and thus does not have a detrimental effect on platelet survival. Using lymphocytic leukemia and non-Hodgkin lymphoma cell lines, in vitro experiments demonstrated that ABT-199 was pro-apoptotic as evidenced by activation of caspases 3 and 7, induction of annexin V expression, and accumulation of cells in the sub G0/G1 phase of the cell cycle. ABT- 199 was shown to inhibit growth of BCL-2-dependent tumors in mouse xenograft models, with complete responses being observed when ABT-199 was used together with rituximab and prolonged response noted with the combination of ABT-199, bendamustine, and rituximab.
Because ABT-199 induced apoptosis with an average EC50 of 3 nM in 15/15 primary CLL samples, the first human clinical trial of ABT-199 was aimed at refractory CLL. Three patients participated in the study. Within 24 hours of drug administration, there was a reduction in palpable lymphadenopathy in all patients and a > 95 percent reduction in peripheral blood lymphocytosis in the two subjects with pretreatment lymphocytosis. Minor, transient decreases in platelet counts were observed, and evidenceof tumor lysis was documented in all three patients.
In Brief
Given the central role of BCL-2 in cancer cell survival, the availability of a specific inhibitor with a favorable therapeutic index would be a valuable addition to our armamentarium as previewed in the clinical trial reported by Souers and colleagues. Meanwhile, the family of both selective and non-selective BCL-2 inhibitors will enable targeting of the anti-apoptotic pathways in different types of cancer2-4 and may afford particular advantages when used in combination with other drug treatments, including alkylators (e.g., bendamustine), antibodies (e.g., rituximab), and tyrosine kinase inhibitors (e.g., dasatinib), as has already been demonstrated in the laboratory.
