VEN resistance can by overcome by activation of the extrinsic apoptotic pathway. (A) Heat map showing IC₅₀ values of sensitive and VEN-resistant Nalm6 cells for 45 compounds: red, IC₅₀ ≥10 μM; yellow, IC₅₀ ≥5 μM; and green, IC₅₀ ≤1 μM. Cumulative results from 3 experiments. (B) Close-up view of the 3 most potent drugs identified for Nalm6 and corresponding Nalm6-VEN–resistant cells. (C) Cell death assay of sensitive and VEN-resistant Nalm6 for TRAIL (48 hours) determined by flow cytometry. Mean ± SD. N = 3. (D) Results from Caspase-Glo 8 Luminescent Assay in sensitive and VEN-resistant Nalm6 cells after treatment with TRAIL (50 ng/mL, 4 hours). N = 1. (E) Viability of sensitive and VEN-resistant Nalm6 cells after incubation with caspase-8 inhibitor Z-IETD-FMK (25 μM, 6 hours) and/or TRAIL treatment (200 ng/mL, 4 hours) determined by flow cytometry. N = 2. (F) Immunoblots for (t)BID, caspase-3, caspase-8, and PARP isoforms in Z-IETD-FMK and/or TRAIL treated cells. N = 2. DMSO, dimethyl sulfoxide.