Chemotherapy resistance remains a formidable challenge in cancer treatment, driving high mortality rates worldwide. Despite significant advancements, it remains unclear whether conserved molecular programs underpin therapy resistance across cancer types.
Here, we integrate single-cell RNA sequencing, spatial transcriptomics, regulatory network modeling, transcription factor binding data, and pharmacologic perturbation across multiple cancer types to define a conserved, proliferative chemoresistant tumor state.
Contrary to the prevailing notion that resistance arises from quiescent or EMT-like phenotypes, we find that resistant tumor cells display elevated G2/M and S-phase activity, enriched expression of E2F and MYC target genes, and activation of DNA repair and PI3K/AKT signaling pathways. We identify the transcription factor MYC as a central regulator of the resistant state, with progressive activation along the resistance trajectory and focal expression in resistant epithelial niches. A novel MYC target, SRM (Spermidine Synthase), emerges as a conserved effector of resistance, promoting polyamine biosynthesis critical for chromatin stability and metabolic resilience. SRM expression correlates with MYC binding and predicts poor patient survival. Functional validation in cell lines, patient-derived organoids and mouse models demonstrate that pharmacologic inhibition of MYC, SRM, or WNT signalling restores chemotherapy sensitivity, suppresses resistance-associated pathways, and reactivates apoptosis. Spatial and survival analyses confirm the clinical relevance of the MYC–SRM axis, establishing it as a druggable module in treatment-refractory cancers.
To our knowledge, this is the first comprehensive study that redefines chemoresistance as a proliferative, MYC-driven state and uncover SRM as a tractable vulnerability, offering new avenues for therapeutic intervention across diverse epithelial malignancies.
Mohammed M. A. Inayatullah, Engin Demirdizen, Zachery Keepers et al.· Genome Medicine· 0 citations
TP53-mutated acute myeloid leukemia (AML) has dismal outcomes with current treatments and represents a critical unmet need. TP53-mutated AML is proposed to be susceptible to immunotherapeutic approaches but, to date, there is no established immunotherapy for this sub-group. Expression of stimulator of interferon genes (STING), a key innate immune driver that activates interferon (IFN) signaling, is decreased by epigenetic silencing or mutation in many cancers, including those with TP53 mutations. Here, we report that response to the next-generation synthetic STING agonist C92 is potentiated in AML cell lines and primary cells with TP53-mutated versus wild-type (WT) cells, representing a previously undescribed vulnerability of these leukemia cells to STING small molecule therapies. Moreover, combining treatment with the DNA methyltransferase inhibitor (DNMTi) decitabine (DAC), significantly increases STING activation, with marked transcriptome-wide increase in repetitive elements (REs) and upregulation of a critical set of interferon-related genes. Cell death in TP53 KO versus WT AML is specifically dependent on innate immune zinc finger NFX1-type containing 1 (ZNFX1) and Z-DNA-binding protein 1 (ZBP1) driving increased cleavage and activation of Receptor-Interacting-Serine/Threonine-Protein Kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL), suggesting mechanisms of necroptosis. Finally, C92 and DAC combination significantly reduces leukemia burden in humanized AML mouse models, accompanied by increased immune responses, including cytokines and cytotoxic T lymphocytes in the leukemia microenvironment. These results support development of clinical trial strategies combining STING agonists with DNMTis for patients with TP53-mutated AML. Summary TP53-mutated AML potentiates effects of novel next-generation STING agonist C92, with unique allosteric and non-cyclic dinucleotide (non-CD) mechanism of action, inducing increased STING activation and cytokine release STING agonists and DNMTis, synergistically increase STING activation with marked transcriptome-wide increase in repetitive elements (REs) and upregulation of a critical set of interferon-related genes in TP53-mutated AML STING agonists induce necroptosis via a STING-ZNFX1-ZBP1-necroptosis axis in TP53-mutated AML. This drug combination reduces leukemia burden, activates immune responses in AML models and supports translation for high-risk AML patients. Statement of Translational Relevance This pre-clinical study identifies a novel therapeutic vulnerability in (TP53)-mutated acute myeloid leukemia (AML), a poor prognosis subtype with a critical unmet need. Novel next-generation STING agonist C92, with unique allosteric and non-cyclic dinucleotide (non-CD) mechanism of action, induces increased STING activation and cytokine release, compared with WT TP53 in AML cell lines and primary cells, and has superior STING activity with respect to several STING agonists currently in clinical studies. Combining C92 treatment with the DNA methyltransferase inhibitor (DNMTi) decitabine (DAC) synergistically increases STING activation, with marked transcriptome-wide increase in repetitive elements (REs) and upregulation of a critical set of interferon-related genes, driving ZNFX1-driven inflammatory necroptotic cell death. Utilizing humanized mouse models, C92 in combination with DAC significantly reduces leukemia burden and enhances cytotoxic T-cell responses in the tumor microenvironment, supporting clinical translation for high-risk AML patients.
K. Tripathi, Lora Stojanovic, Zahra Gohari et al.· bioRxiv· 0 citations
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