Secondary resistance to naratuximab emtansine determines elevated p-AKT, p-BCL2, and MCL1 and increased sensitivity to idelalisib and venetoclax, which can also overcome the resistance to the ADC. (A) Immunoblotting for AKT/p-AKT, BCL2/p-BCL2, and MCL1 in SU-DHL-4 parental and resistant. Representative of 2 independent experiments. (B) Data on the bar plots represent the protein quantification (normalized to vinculin and dimethyl sulfoxide [DMSO]). (C) MTT assay (72 hours) in resistant and parental cells of SU-DHL-4 upon increasing doses of venetoclax (upper) or idelalisib (bottom). Bar plots correspond to IC₅₀ values of resistant (red) and parental (blue) lines. ∗P < .05. (D) Annexin-V/PI staining by FACS obtained in naratuximab emtansine–resistant and parental SU-DHL-4 exposed to naratuximab emtansine (625 pM), venetoclax (25 nM), or idelalisib (625 nM). Representative MTT plots showing the combination of naratuximab emtansine with venetoclax (E) or idelalisib (F) in parental (left) and resistant (right) cells of SU-DHL-4. ∗P < .05. PI, Propidium Iodide