Biology subjects

Ayoub, E.

Publications and source records attributed to Ayoub, E..

3 recordsLinked to original sources

bioRxiv2025

Macrophage-secreted Pyrimidine Metabolites Confer Chemotherapy Resistance in Acute Myeloid Leukemia (AML)

The tumor microenvironment (TME) programs cancer cells to influence therapeutic responses. Macrophages residing in TME switch from pro-phagocytic to tumor-promoting and immunosuppressive phenotypes as cancer develops. While these pro-tumor functions of macrophages are associated with poor outcomes, the underlying mechanisms by which bone-marrow (BM)-associated macrophages fuel myeloid malignancy and their precise contribution to relapse remain undissected. Here, we show expansion of monocyte/macrophage population in leukemia patients post-chemotherapy relapse, and spatial proximity of macrophages to leukemia blasts in the BM niche. This proximity proved functionally consequential--depletion of macrophages delayed leukemia relapse post cytarabine (AraC), a frontline chemotherapy, in patient-derived xenografts (PDX) and syngeneic leukemia models. Mechanistically, a pyrimidine metabolite, deoxycytidine (dC), secreted by BM macrophages, is taken up by leukemia cells to directly inhibit deoxycytidine kinase (DCK) to hamper AraC activation and subsequent resistance in a cell non-autonomous manner. Diagnosis AML patients exhibited significantly higher circulating dC levels than healthy donors, and dC levels further increased following chemotherapy. SAMHD1, which catalyzes deoxynucleoside triphosphates (dNTPs) into deoxynucleoside, was highly abundant in macrophages and mediated dC accumulation. Blockade of dC production in mouse and human macrophages via genetic and pharmacological inhibition of SAMHD1 or DHODH, a critical enzyme in pyrimidine synthesis, restored AraC sensitivity. Combination with DHODH inhibitors significantly delayed AraC relapse in human PDX and mouse syngeneic AML models. Collectively, we identify a metabolic immune-leukemia crosstalk in which SAMHD1high macrophages mediates chemoresistance by secreting pyrimidine metabolites and propose macrophage metabolic reprogramming as a tractable strategy to overcome TME-driven chemoresistance in myeloid leukemia.

cancer biology↗

bioRxiv2025

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

TP53 mutations across multiple cancers, including acute myeloid leukemia (AML), are associated with poor outcomes irrespective of treatment modality. However, druggable vulnerabilities beyond canonical p53 targets remain largely unexplored. We identify BIRC5 (encodes survivin), an inhibitor of the apoptosis protein (IAP) family, as a novel vulnerability in TP53 mutant AML using an unbiased, comprehensive multiomics approach -- whole-genome CRISPR knockout screen, bulk and single-cell RNA-seq, proteomics, and high-throughput drug screen. Mechanistically, BIRC5 deletion in AML restored caspase-9 and -3/7 activity and downregulated other IAPs, implicating BIRC5 as the central post-mitochondrial regulator for blocking apoptosis. p53 stabilization suppressed BIRC5 selectively in TP53 wild-type AML, explaining BIRC5 upregulation in TP53 mutant lines and AML primary tumors (n > 700). Longitudinal single-cell RNAseq (n = 22 pairs) revealed expansion of BIRC5high stem and progenitor leukemia clones in TP53 mutant AML patients post-VenAza therapy. Survivin and IAP inhibitors emerged as top combination partners with VenAza in TP53 mutant AML cells and showed potent in vivo leukemic blast inhibition in cell line and patient-derived xenograft models along with primary tumors. Beyond AML, BIRC5 was upregulated broadly across 17 of 25 TP53 mutant cancers in the TCGA cohort, and combination with survivin inhibitors overcame chemotherapy resistance in TP53 deficient triple negative breast and colorectal cancers. These findings define BIRC5 as a critical, targetable dependency and unveil survivin/IAP inhibition as a promising therapeutic axis to overcome p53-related resistance across both hematologic and solid malignancies. Key PointsO_LIBIRC5 upregulation is a novel dependency in TP53 mutant AML that mediates therapy resistance by evasion of apoptosis. C_LIO_LICombination with Survivin/IAP inhibitors overcomes venetoclax/azacitidine resistance in TP53 mutant AML. C_LI

cancer biology↗

bioRxiv2025

Dual MYC and GSPT1 Protein Degrader for MYC-Driven Cancers

Direct targeting of the oncoprotein MYC has long been attempted in cancer therapy, with limited success. We here identify a novel co-regulatory feedback loop of MYC and G1 to S phase transition protein 1 (GSPT1), where MYC promotes transcription of GSPT1, and GSPT1 senses stop codon of MYC to promote its translation. We report on the first-in-class dual MYC/GSPT1 protein degrader, GT19630. GT19630 significantly induced integrated stress response, abrogated oxidative phosphorylation through inhibition of the TCA cycle and induced cell death. Protein degradation of MYC was critical for efficacy of GT19630. GT19630 induced profound anti-proliferative effects and apoptosis agnostic to TP53 in a broad range of cancer cells, and is highly active in vivo in multiple, therapy-resistant hematologic and solid tumor models. Dual MYC/GSPT1 degradation was well tolerated in humanized CrbnI391V mice. In conclusion, we propose a novel treatment approach by directly targeting the MYC-GSPT1 axis in MYC-driven cancers. Statement of significanceMYC has been considered an undruggable protein. We found a targetable, novel positive co-regulatory feedback of MYC and GSPT1, a key translation terminator. The dual MYC/GSPT1 degrader GT19630 is highly active in MYC-driven tumors, with moderate effects on humanized Crbn mice, providing opportunities to improve treatment outcome of MYC-driven cancers.

cancer biology↗