AARS1-catalyzed H4K12 lactylation promotes HCC resistance to targeted therapy by activating RAPGEF3-RAP1 signaling.

AKAP13 regulates GLI1/ULK1 axis and drive tumor resistance to next-generation HER2-targeted therapies.

Histone H3K18 Lactylation Promotes the Malignant Progression of Wilms Tumor via a PSRC1/AKT/HIF‐1α Positive Feedback Loop

ABSTRACT Nephroblastoma, also known as Wilms tumor (WT), is the most common pediatric renal malignancy. Current treatment regimens exhibit limited efficacy in high‐risk patients and are associated with long‐term adverse effects. Through gene set enrichment analysis (GSEA) and validation using clinical specimens, we identified aberrant glycolytic activity in WT, which drives lactate accumulation. Lactate is not merely a metabolic byproduct but also a critical epigenetic regulator that mediates histone lactylation; however, its functional role in WT remains uncharacterized. In this study, we found that the hyperlactate microenvironment induced by abnormal glycolysis in WT significantly upregulates the level of histone H3K18 lactylation (H3K18la). Functional experiments confirmed that histone lactylation promotes WT cell proliferation and migration. Mechanistically, H3K18la, catalyzed by its “writer” p300, directly marks the promoter region of the downstream target gene PSRC1 and transcriptionally activates its expression. PSRC1 then acts as a key “molecular competitor,” binding to AKT in a competitive manner with the phosphatase PTEN. This interaction relieves PTEN‐mediated dephosphorylation inhibition of AKT, thereby activating the AKT/mTOR signaling pathway and enhancing the protein stability of its downstream effector HIF‐1α. Concurrently, HIF‐1α functions as a transcription factor to directly bind to the PSRC1 promoter, synergizing with H3K18la to further amplify PSRC1 transcription. In summary, this study identifies a positive feedback loop: “H3K18la→PSRC1→AKT/mTOR→HIF‐1α→PSRC1.” This mechanism dynamically links tumor metabolic abnormalities, histone modifications, and key oncogenic signaling pathways, which collectively drive the malignant progression of WT. These findings provide a novel theoretical basis for the stratified diagnosis and targeted therapy of WT.

TBX15 increases ferroptosis to overcome sorafenib resistance via HERC5-mediated cGAS ISGylation in hepatocellular carcinoma.

The drug resistance to targeted therapy in patients with advanced hepatocellular carcinoma (HCC) is gradually increasing. Thus, it is very important to further examine the molecular signaling pathways related to HCC and the corresponding targeted therapy. The study identified a significant association between low TBX15 expression and sorafenib resistance in HCC. TBX15 increased sorafenib sensitivity in HCC cells by inducing ferroptosis in vivo and vitro experiments. Mechanistically, TBX15 promoted the secretion of mitochondrial DNA (mtDNA) into the cytoplasm through the opening of the mitochondrial permeability transition pore, then stimulated the cGAS/STING pathway due to the increased cytosolic mtDNA. TBX15 binds to the HERC5 promoter region, increasing cGAS ISGylation and enhancing its stability. Furthermore, the activation of cGAS/STING pathway increased ferroptosis in HCC cells. Our research underscores TBX15's potential to counteract sorafenib resistance and establishes the TBX15-cGAS/STING axis as a key regulator in HCC pathobiology.

A novel peptide encoded by circTLL1 drives osimertinib resistance in lung cancer by modulating the NT5C2/Ras/PI3K axis.

BACKGROUND Acquired resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor, remains a major clinical challenge in the treatment of non-small cell lung cancer (NSCLC). Although circular RNAs (circRNAs) have been increasingly implicated in drug resistance, most studies have focused on their canonical role as microRNA sponges, while their capacity to encode functional micropeptides remains largely unexplored. This study aimed to identify novel circRNAs involved in osimertinib resistance and to characterize their regulatory functions at the protein level. METHODS Osimertinib-resistant (OR) NSCLC cell lines were established and validated. High-throughput RNA sequencing was performed to compare the circRNA expression profiles between parental and OR cells. The function of the candidate circRNA was assessed through a series of in vitro and in vivo experiments, including cell viability assays, apoptosis analysis, and xenograft mouse models. Mechanistic investigations involved mass spectrometry, co-immunoprecipitation and western blotting to explore its protein-coding potential and downstream signaling pathways. RESULTS We identified a novel circRNA, termed circTLL1, that was stably and significantly upregulated in OR-NSCLC cells. Functionally, overexpression of circTLL1 promoted osimertinib resistance, whereas its knockdown restored drug sensitivity both in vitro and in vivo. Mechanistically, we discovered that circTLL1 harbors an open reading frame (ORF) that is translated into a novel 90-amino-acid protein, which we designated circTLL1-90aa. Further investigation revealed that circTLL1-90aa directly interacts with and promotes the degradation of 5'-nucleotidase, cytosolic II (NT5C2), thereby uncoupling nucleotide metabolism from its normal regulatory constraints. The consequent downregulation of NT5C2 leads to elevated GTP levels and leading to the sustained activation of the downstream Ras/PI3K/AKT signaling pathway. CONCLUSION Our findings unveil a previously unrecognized circRNA/micropeptide/metabolism cascade underlying osimertinib resistance. The identification of the circTLL1-90aa/NT5C2/Ras/PI3K axis not only expands the functional repertoire of the non-coding genome but also provides new insights into the complexity of drug resistance. Given its selective upregulation in resistant cells, circTLL1-90aa holds promise both as a predictive biomarker for treatment stratification and as an actionable therapeutic target, offering a novel strategy to overcome osimertinib resistance in NSCLC patients.

USP20-mediated PGAM1 stabilization promotes glycolysis and confers osimertinib resistance in non-small cell lung carcinoma

Abstract B031: MetAP2 inhibition by evexomostat (SDX-7320) decreases EZH2 and c-Myc and significantly prolongs survival in enzalutamide-resistant and neuroendocrine prostate cancer models

Androgen receptor pathway inhibitors (ARPIs) improve outcomes for patients with mCRPC. However, development of resistance to ARPIs is a significant clinical issue associated with the emergence of aggressive variant prostate cancer (AVPC), and consequently there is an urgent need for novel, AR pathway-independent therapies. Expression of the metalloprotease methionine aminopeptidase 2 (METAP2) has been correlated with increased mCRPC aggressiveness: high expression was reported in dedifferentiated phenotypes, including NEPC/AVPC. METAP2 regulates protein translation, post-translational modifications and has a clinically validated role inhibiting angiogenesis. METAP2 also has tumor-specific functions coordinating plasticity, vascular mimicry, and hypoxia response. Evexomostat (SDX-7320) is a prodrug of a highly potent, novel METAP2 inhibitor which has completed a phase I safety study in late-stage cancer patients (NCT02743637) and is currently being clinically investigated in patients with metastatic breast cancer (NCT05570253, NCT05455619). It was hypothesized that SDX-7320 would demonstrate anti-tumor efficacy in non-clinical prostate cancer cell-derived xenograft and patient-derived xenograft (PDX) models of ARPI-resistant CRPC and AVPC. SDX-7320 (12 or 8 mg/kg, subcutaneous dosing, every four days) was tested in NSG mice with LNCaP xenografts in intact, castrated, and CRPC models. SDX-7320 treatment was also evaluated in LuCaP35.CR PDX xenografts in castrate mice alone as well as in combination with enzalutamide following development of resistance to enzalutamide. SDX-7320 was also tested in the LTL545, LUCAP49 and LTL331R (AR-negative, NE-positive) models of AVPC. Tumor growth was assessed and following dissection subsequently analyzed for transcriptomic (RNAseq), protein (Western blot) or histological differences (H&E staining, CD34 IHC). SDX-7320 treatment significantly reduced tumor volume in every model and at every PC stage investigated, alone and in combination with enzalutamide (in enzalutamide-resistant tumors), as well as in the LTL545, LUCAP49 and LTL331R AVPC models. Reduced angiogenesis marker CD34 staining was observed in all tumors from SDX-7320-treated mice. Survival of mice treated with SDX-7320 was significantly enhanced, regardless of model phenotype. Downstream analyses of bulk RNAseq and proteomics showed model-specific changes to plasticity regulators c-Myc and the enhancer of zeste homolog 2 (EZH2) indicating an effect of METAP2 inhibition on prostate cancer cellular differentiation. These results show that inhibition of METAP2 with SDX-7320 is a novel approach to treat ARPI-resistant as well as aggressive forms of prostate cancer warranting immediate clinical translation. Building upon the non-clinical data in models of AVPC presented here, combined with the body of clinical experience with SDX-7320 in past and ongoing clinical trials, planning is underway to conduct a pilot clinical trial with SDX-7320 in men with AVPC. Peter Cornelius, Devina Laurencia, Jennifer H. Gunter, Anja Rockstroh, Benjamin A. Mayes, Pierre Dufour, Bradley J. Carver, James M. Shanahan, Colleen C. Nelson. MetAP2 inhibition by evexomostat (SDX-7320) decreases EZH2 and c-Myc and significantly prolongs survival in enzalutamide-resistant and neuroendocrine prostate cancer models [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B031.