TargetableBIRC5dependency in therapy-resistantTP53mutated acute myeloid leukemia

TP53mutations confer treatment resistance across multiple cancers. Mechanisms of therapy resistance, beyond affecting transactivation of BCL-2 family genes, remain a mystery. Here, we report thatTP53mutated AML, triple negative breast cancer, and colorectal cancer escape therapy-induced apoptosis due to inability to activate caspase-3/7, despite having normal mitochondrial outer membrane permeabilization (MOMP) induction. To identify post-MOMP determinants of therapy resistance inTP53mutated AML, we applied a multiomics approach – whole-genome CRISPR screen, bulk/single-cell RNAseq, and high-throughput drug screen.BIRC5, encoding survivin, was selectively upregulated in paired hematopoietic stem/multipotent progenitor cells fromTP53mutant AML patients, with further enrichment after venetoclax-azacitidine (VenAza) relapse. Critically,BIRC5was also upregulated in 17 of 26TP53mutant TCGA cancers. Genetic ablation ofBIRC5resensitizedTP53mutated AML to standard therapy by restoring caspase activation, validating therapeutic relevance. Importantly, targeting IAPs and survivin using clinically relevant inhibitors overcame VenAza resistance ofTP53mutant tumorsin vivo, achieving sustained AML suppression. Combination with survivin inhibitors also overcame chemotherapy resistance inTP53deficient solid cancers. Together, we discovered that wild-typeTP53is required in post-MOMP signaling and thatBIRC5dependency is an effective therapeutic target for poor prognosis,TP53mutated cancers.