SRA

TP53-mutant blood cancers remain a major clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins to promote cancer cell apoptosis. Despite acting downstream of TP53, functional TP53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report TP53 can be activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, which leads to induction of BH3-only proteins, thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feed-forward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. The therapeutic barrier imposed by defects in TP53 could be overcome by direct activation of the cGAS/STING pathway, which promotes apoptosis of blood cancer cells through TP53-independent BH3-only protein upregulation. Combining clinically relevant STING agonists with BH3-mimetics efficiently killed TP53-mutant mouse B lymphoma, human NK/T lymphoma and acute myeloid leukemia cells. This represents a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic. Overall design: To examine the downstream efffects of apoptosis-inducing drugs, mouse Eu-Myc lymphoma cells were treated with the MCL-1 inhibitor S63845 and/or the STING agonist diABZI for 24 h in the presence of caspase inhibitors and RNAseq performed. For STING agonist comparisons, 2 independent Eu-Myc lymphoma cell lines were included. For MCL-1 inhibitor (S63845) comparisons, 3 independent Eu-Myc lymphoma cell lines were included. The study includes parental lymphomas (control, containing Cas9 and a non-targeting sgRNA (hBim)), as well as Trp53 KO and Sting KO derivatives, generated by CRISPR/Cas9.