Idasanutlin/venetoclax combinations partially overcome drug resistance in monocytic leukemias. (A) The graphs show the mean viabilities of primary patient samples treated with dose gradients of idasanutlin (Ida) and venetoclax (ven), in combination with the indicated antagonists or inhibitors, as determined by MTS assays. The gray line is the predicted additive efficiency line that was calculated using the Excess over Bliss formula. The inhibitors were evaluated across a total of 9 concentrations with the highest dose being indicated on the right. The remaining 8 doses were prepared using 1:2 or 1:3 serial dilutions. (B) The drug AUCs for ven, doramapimod, and their combination based on 23 M4/M5 and 23 M0/M1 patient samples from the Beat AML cohort are shown. (C) The bar graphs show the AUCs from panel B. Significant differences were determined using multiple-comparison analysis of variance tests. (D) Graphs depict the viabilities of primary leukemia blasts from 2 patients cultured with monocytes isolated from 1 M5 leukemia sample (22-111) in the presence of Ida (500 nM) or ven (30 nM), in combination with the indicated drugs (1 μM for the inhibitor, 100 ng/mL for anakinra), for 2 days as determined by annexin V/PI. Mono, CD14⁺ monocytes and monocyte precursors isolated from an AML sample (22-111). (E) The schematic outlines the experimental workflow for generating and treating an in vivo mouse leukemia xenograft model that was engrafted with M4 primary leukemia cells from 3 donors. C stands for the IRAK4 inhibitor CA-4948, and A stands for the IL-1R antagonist anakinra. (F) The Kaplan-Meier curve demonstrates the survival percentages of mice treated with different reagents. Significant differences were determined using a log-rank test.