Identification of MALT1 as a target to overcome OAsIs resistance. (A) RNA-seq expression of the 16 genes of the MCL_R16 resistance signature in BCL2A1⁺CARD11^WT cell lines (SP53, NTS3, REC-1) and BCL2A1⁺CARD11^MUT cells (001-024, OCILY3, SUDHL16) treated 24 hours with the BTK inhibitor ibrutinib (500 nM) (left panel) or the MALT1 inhibitor MLT-748 (1 μM) (right panel). Mann-Whitney test; ∗∗∗∗P < .0001. BCL2A1 is shown in red. Genes from bottom to top: CCL4, FABP5, CCL3, BCL2A1, CCL22, NPW, NME1, PTP4A3, PLEK, CD83, SRM, CALR, PA2G4, NCL, SDF2L1, DDX21. (B-C) CARD11, HOIL1, and BCL2A1 protein expression were assessed by immunoblot in indicated cells treated or not with the BTK inhibitor ibrutinib (500 nM) or the MALT1 inhibitor MLT-748 (1 μM) for 24 hours. The arrow highlights cleaved form of HOIL1. (D) Synergy score (HSA method) computed for 4 cell lines treated with venetoclax and MLT-748 for 48 hours. Unpaired t-test; ∗P < .05. Detailed results are represented in supplemental Figure 8C. The mean and SD of 3 independent experiments are represented. (E) Tumor weights at day 16 for CARD11^D230N MCL PDX (DFBL44685-v2) treated with the BCL2-i venetoclax (2 nM), the MALT1-i JNJ-67856633 (250-500 nM) or both. n = 5 per group. Mann-Whitney test; ∗∗P < .01. Representative pictures of engrafted tumors in CAM at day 16 are shown in the right panel. n.s., not significant.