BH3-targeted inhibitors drive specific resistance in human cell lines, which can be overcome with alternating or combining inhibitors. BH3-targeted inhibitors.

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BH3-targeted inhibitors drive specific resistance in human cell lines, which can be overcome with alternating or combining inhibitors. BH3-targeted inhibitors drive specific resistance in human cell lines, which can be overcome with alternating or combining inhibitors. A, Human MV-4-11 cells were isolated from the bone marrow of premorbid vehicle-treated mice at D28, and VU661013-treated mice at D42 and were tested ex vivo with VU661013 (mean ± SEM; n = 3). B, Naïve MV-4-11 cells (parent) and cells made resistant to VU661013 (VU661013-resistant) or venetoclax (VEN-resistant) were tested in growth inhibition assays with VEN and (C) VU661013 treatment. D, VU661013-resistant MV-4-11 cells treated with VU661013, VEN, or a combination of VU661013 and VEN, concentrations of each compound (Cmpd) are noted on the x-axis; E, VEN-resistant MV-4-11 cells treated with VU661013, VEN, or a combination of VU661013 and VEN, concentrations of each compound (Cmpd) are noted on the x-axis. For B–E, data shown as mean ± SEM (n = 3). F, The combination of VEN and VU661013 in vivo resulted in a survival benefit in an MV-4-11 AML model mice via Kaplan–Meier analysis. Statistical significance was calculated using log-rank (Mantel–Cox) test (P < 0.001; n = 5 per arm). G, The combination of VEN and VU661013 in vivo significantly decreased tumor burden in an MOLM-13 AML xenograft. Per arm vehicle (n = 7), VEN (n = 9), VU661013 (n = 6), and VU661013/VEN (n = 8). A nonparametric, unpaired, two-tailed t test was used to calculate significance. Data are combined from two independent experiments. H, IHC of bone marrow (femur) and spleen (20×), stained with monoclonal antibody for hCD45 in experimental mice. Scale bars, 50 μm. Haley E. Ramsey et al. Cancer Discov 2018;8:1566-1581 ©2018 by American Association for Cancer Research