These results uncover a metabolism-epigenetics–cell cycle interface that may represent a therapeutic vulnerability in EGFR-mutant LUAD and identify a glycolysis–H4K8la–GAS2L3 axis that drives noncanonical cell-cycle reprogramming independently of classical Cyclin–CDK activation, thereby promoting acquired osimertinib resistance.
Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have markedly improved outcomes in EGFR-mutant lung adenocarcinoma (LUAD), yet acquired resistance to the third-generation inhibitor osimertinib remains inevitable. Although metabolic reprogramming is increasingly recognized as a driver of therapeutic resistance, the epigenetic consequences of lactate accumulation and their functional relevance in osimertinib resistance are poorly understood. Here we report that osimertinib-resistant LUAD cells exhibit enhanced glycolytic flux, increased intracellular lactate levels, and elevated histone H4 lysine 8 lactylation (H4K8la). Integrative transcriptomic analysis revealed significant enrichment of cell-cycle–associated pathways in resistant tumors, despite downregulation of canonical Cyclin B1 and Cyclin D1. Among the upregulated genes, GAS2L3 emerged as a prominent candidate. Genome-wide CUT&Tag profiling demonstrated enrichment of H4K8la at the GAS2L3 promoter, which was confirmed by ChIP–qPCR. Functionally, GAS2L3 overexpression accelerated S/G2–M progression and promoted proliferation under drug pressure, whereas its silencing induced cell-cycle arrest and restored osimertinib sensitivity both in vitro and in xenograft models. Notably, resistant cells displayed elevated P53 expression without induction of its canonical effector P21, indicating checkpoint uncoupling and a noncanonical mode of cell-cycle regulation. Mechanistically, glycolysis inhibition reduced H4K8la and GAS2L3 expression and partially re-sensitized resistant cells, while exogenous lactate restored H4K8la levels and resistance phenotypes, establishing a metabolically driven epigenetic circuit. Clinically, high GAS2L3 expression was associated with shorter progression-free survival in osimertinib-treated patients. Collectively, our findings identify a glycolysis–H4K8la–GAS2L3 axis that drives noncanonical cell-cycle reprogramming independently of classical Cyclin–CDK activation, thereby promoting acquired osimertinib resistance. These results uncover a metabolism-epigenetics–cell cycle interface that may represent a therapeutic vulnerability in EGFR-mutant LUAD.
Target neutralization of SAA1 synergized robustly with osimertinib to reverse immunosuppressive remodeling and induce profound tumor regression in multiple preclinical models, highlighting SAA1 neutralization as a tractable combinatorial strategy to enhance EGFR-TKI efficacy in LUAD.
Jun-Kan Zhu, Shencheng Ren, Tao Cheng et al.· Journal of Experimental &...· 0 citations
Osteosarcoma continues to exhibit poor survival outcomes due to chemoresistance and metastasis, with metabolic reprogramming and ferroptosis resistance being key features of tumor heterogeneity, yet their upstream regulators remain poorly defined. NFS1, a cysteine desulfurase essential for iron–sulfur cluster biogenesis, protects multiple cancers from ferroptosis, but its role in osteosarcoma is unknown. In this study, we performed a transcriptomic meta-analysis and found that NFS1 expression was significantly upregulated in osteosarcoma tissues, with further elevation in metastatic lesions, and high NFS1 expression correlated with poor overall survival. Genome‑wide CRISPR screening data revealed a marked NFS1 dependency in osteosarcoma cell lines. Functionally, NFS1 promoted cell proliferation, migration, and invasion, whereas its knockdown suppressed these phenotypes. Using single‑cell RNA sequencing data from 27 osteosarcoma specimens, we applied a multi‑algorithm glycolytic scoring framework and observed NFS1 enrichment in highly glycolytic malignant cells, along with an association with PI3K/AKT/mTOR pathway activation. Mechanistically, NFS1 selectively enhanced PI3K, AKT, and mTOR phosphorylation without altering total protein levels, and upregulated GPX4, a central ferroptosis suppressor, leading to elevated ferroptosis resistance scores in NFS1‑high malignant cells. Collectively, these findings identify a previously unrecognized NFS1–PI3K/AKT/mTOR–GPX4 regulatory axis in osteosarcoma, linking metabolic reprogramming to ferroptosis resistance, and suggest that NFS1 functions as an oncogenic driver, as well as a promising prognostic biomarker and therapeutic target in osteosarcoma.
Yu-Nan Man, Jing-Tang Li, Tao Zhang et al.· Functional & Integrative Gen...· 0 citations
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
Flap endonuclease 1 (FEN1), a key enzyme in DNA metabolism, exhibits oncogenic properties in various cancers. However, its functional role and underlying mechanisms in lung adenocarcinoma (LUAD) progression and tumor immunity remain poorly defined. Here, we demonstrate that FEN1 is significantly upregulated in LUAD tissues and serves as an independent prognostic factor for poor survival. Genetic depletion of FEN1 suppressed LUAD cell proliferation by inducing G0/G1 cell cycle arrest and cellular senescence, while significantly impairing migration and invasion capabilities. Mechanistically, integrated proteomic and molecular analyses revealed that FEN1 knockdown disrupts the carboxyl-terminal subunit of mucin 1 (MUC1-C)/PI3K/AKT autoregulatory loop, a critical driver of oncogenic signaling. Furthermore, FEN1 downregulation inhibited the MUC1-C/p65/ programmed death-ligand 1 (PD-L1) signaling axis, thereby alleviating tumor-mediated immunosuppression. This was evidenced by enhanced antitumor immunity, characterized by the local expansion of CD4
+
T cells and restored effector function of CD8
+
T cells, both in vitro and in vivo. Mechanistically, independent of its nuclease activity, FEN1 interacts with the N-terminus of eukaryotic translation initiation factor 4A3 (EIF4A3) to facilitate its binding to MUC1-C mRNA. Specifically, FEN1 is required for EIF4A3-mediated maintenance of both the transcript stability and translation efficiency of MUC1-C. Clinically, FEN1, MUC1-C, and PD-L1 are coordinately upregulated in LUAD tissues, and their co-expression predicts poor patient survival irrespective of EGFR mutation status. Our findings establish the FEN1/EIF4A3/MUC1-C axis as a novel mechanism driving LUAD progression by concurrently regulating intrinsic malignancy and extrinsic immune evasion, presenting FEN1 targeting as a promising dual-hit therapeutic strategy.
Min Wu, Ben-Meng Wu, Xue-Bing Yan et al.· Cell Death & Disease· 0 citations
While chemoresistance in non-small cell lung cancer (NSCLC) cells has historically been attributed to permanent genetic mutations, emerging evidence highlights the role of nongenetic transcriptional plasticity and ‘drug-tolerant persister’ cells. To systematically map these epigenetic vulnerabilities, we utilized a genome-wide CRISPR interference library to screen wild-type TP53 NSCLC (A549) cells under carboplatin selection. Using the DrugZ algorithm and subsequent pathway enrichment analyses, this screen revealed that transcriptional suppression of interstrand crosslink DNA repair networks, including the Fanconi anemia pathway, markedly sensitized cells to carboplatin. Unexpectedly, transcriptional silencing of TP53 and its downstream target CDKN1A emerged as the strongest drivers of resistance, enabling cells to bypass therapy-induced senescence and maintain their proliferative potential later. To validate these findings in a clinically relevant context, we established a chronic carboplatin-resistant cell model (A549CarboR cells). A549CarboR exhibited a reduction in TP53 transcripts, along with decreased H3K27 acetylation and increased DNA hypermethylation on its promoter. Epigenetic remodeling using the DNA methyltransferase inhibitor (DNMTi) was associated with unblocking TP53 transcription, restored p53 signaling, and resensitization of resistant cells to carboplatin. Conversely, histone deacetylase inhibitors induced CDKN1A transcription to bypass TP53, indicating distinct epigenetic circuits. Collectively, the results demonstrate for the first time that TP53 expression is dynamically regulated at the transcriptional level through promoter methylation related to the drug tolerance. These insights emphasize that epigenetic silencing, rather than exclusive genetic loss-of-function, contribute to platinum resistance and underscore the therapeutic potential of pairing platinum regimens with DNMTi to target the transcriptomic plasticity of persistent cancer cell populations.
Sojung Ha, Woo-Young Kim· Biomolecules & Therapeutics· 0 citations
ABSTRACT Recurrence and progression remain major clinical challenges in bladder cancer (BC), yet the mechanisms linking glycolysis to persistent malignant states remain incompletely defined. Here, we identify alanyl tRNA synthetase 1 (AARS1) as a clinically relevant driver of aggressive and recurrent BC. AARS1 is upregulated in BC tissues, enriched in muscle invasive and recurrent tumors, and associated with unfavorable survival. Functionally, AARS1 promotes proliferation, epithelial mesenchymal transition, invasion, apoptosis resistance, tumor growth, and lung colonization. Mechanistically, AARS1 enhances phosphoinositide 3 kinase (PI3K) pathway output, glycolytic flux, and lactate production. Increased lactate availability is linked to histone H3 lysine 27 lactylation (H3K27la) enrichment at the hexokinase 2 (HK2) promoter, increased chromatin accessibility, and HK2 transcriptional activation, supporting an HK2 centered metabolic and epigenetic reinforcement program. HK2 perturbation attenuates AARS1 associated glycolytic and malignant phenotypes. Through structure guided screening and surface plasmon resonance validation, we further identified eltrombopag as an AARS1 binding compound that pharmacologically suppressed the AARS1 associated PI3K, glycolysis, lactate, H3K27la, and HK2 program and restrained tumor progression in preclinical models. These findings define an AARS1 associated metabolic and epigenetic program in BC and nominate AARS1 targeting strategies as a direction for further therapeutic development.
Qin Yuan, Tianbao Song, Yipeng He et al.· Advancement of science· 0 citations
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