Targetable BIRC5 dependency in therapy-resistant TP53 mutated acute myeloid leukemia

  • bioRxiv. 2025 May 22:2025.05.17.654633. doi: 10.1101/2025.05.17.654633.
Ahmed M Mamdouh ,  Fang Qi Lim ,  Yang Mi ,  Elyse A Olesinski ,  Cheryl Gek Teng Chan ,  Shaista Jasdanwala ,  Xiao Xian Lin ,  Yichen Wang ,  Jordan Yong Ming Tan ,  Karanpreet Singh Bhatia ,  Valeriia Sapozhnikova ,  Chuqi Wang ,  Aarthi Nivasini Mahesh ,  Daniel Tan En Liang ,  Nishtha Chitkara ,  Philipp Mertins ,  Leah Hogdal ,  Brandon D Brown ,  Torsten Haferlach ,  Camille Lobry ,  Coleman Lindsley ,  Alexandre Puissant ,  Han Kiat Ho ,  Sanjukta Das ,  Anthony Letai ,  Steven M Kornblau ,  Jan Krönke ,  Edward Ayoub ,  Koji Itahana ,  Michael Andreeff ,  Shruti Bhatt
PMID: 40475516 DOI: 10.1101/2025.05.17.654633
Abstract

TP53 mutations confer treatment resistance across multiple cancers. Mechanisms of therapy resistance, beyond affecting transactivation of Bcl-2 Family genes, remain a mystery. Here, we report that TP53 mutated 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 in TP53 mutated 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 from TP53 mutant AML patients, with further enrichment after venetoclax-azacitidine (VenAza) relapse. Critically, BIRC5 was also upregulated in 17 of 26 TP53 mutant TCGA cancers. Genetic ablation of BIRC5 resensitized TP53 mutated AML to standard therapy by restoring Caspase activation, validating therapeutic relevance. Importantly, targeting IAPs and Survivin using clinically relevant inhibitors overcame VenAza resistance of TP53 mutant tumors in vivo , achieving sustained AML suppression. Combination with Survivin inhibitors also overcame chemotherapy resistance in TP53 deficient solid cancers. Together, we discovered that wild-type TP53 is required in post-MOMP signaling and that BIRC5 dependency is an effective therapeutic target for poor prognosis, TP53 mutated cancers.

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