OncoTargets and therapy最新文献

Colorectal cancer (CRC) ranks as the third most prevalent malignancy globally based on recent epidemiological studies. In China, the rising incidence and mortality rates of CRC have underscored the importance of elucidating its pathogenic mechanisms, which remain major focus in current biomedical research. Ferroptosis, a regulated cell death process driven by iron-dependent lipid peroxidation, is closely associated with disruptions in iron homeostasis, lipid metabolism, and amino acid metabolism. This unique iron-catalysed death process plays a crucial role in both tumor initiation and malignant progression by disturbing cellular redox imbalance. The cystine/glutamate antiporter SLC7A11 (also known as xCT) has been identified as a central regulator of ferroptosis susceptibility. The tumor suppressor p53 and its associated microRNAs modulate ferroptotic responses through regulation of SLC7A11 expression, forming a critical axis in oncogenic transformation and metastasis. However, the precise role of SLC7A11 in CRC-particularly its context-dependent dual functions as both a tumor promoter and a therapeutic vulnerability-remains a critical unanswered question. This review aims to systematically summarize current advances in understanding the multiple roles of SLC7A11 in CRC-related ferroptosis pathways and to evaluate emerging therapeutic strategies targeting this axis. Importantly, we also underscore the existing knowledge gaps and outline future research directions essential for leveraging this unique molecular pathway to improve patient outcomes.

[This retracts the article DOI: 10.2147/OTT.S116509.].

Purpose: Transcription factor MYB proto-oncogene like 2 (MYBL2) is involved in cell cycle regulation and proliferation, and it has been implicated in various cancers. However, its expression pattern and clinical significance in hepatocellular carcinoma (HCC) are unclear. Therefore, the aim of this study was to evaluate the tissue expression of MYBL2 in patients with HCC and evaluate associations with clinicopathological factors and prognosis.

Patients and methods: We enrolled 88 patients with HCC who underwent hepatectomy from October 2023 to January 2025 and analyzed MYBL2 expressions in non-tumorous and tumorous tissue samples using immunohistochemistry. The patients were then categorized into high and low expression groups, and clinicopathological factors were compared. Cox proportional hazard regression and Kaplan-Meier survival analyses were used to explore the prognostic significance of MYBL2 expression.

Results: MYBL2 immunohistochemistry score was significantly associated with survival (p for trend = 0.038). Kaplan-Meier analysis demonstrated that those with a high MYBL2 expression were associated with lower overall survival compared to those with a low MYBL2 expression (p = 0.029). An independent association was found between high MYBL2 expression in tumorous tissues and poor overall survival (p = 0.047). However, multivariate analysis indicated that MYBL2 expression was not an independent risk factor for overall survival.

Conclusion: The results indicated an association between MYBL2 and HCC prognosis, suggesting that it could be used as a prognostic biomarker and potentially be a therapeutic target. Further research is required to clarify the molecular mechanisms by which MYBL2 drives tumor progression and to explore its potential in targeted therapy for HCC.

Therapeutic options for NSCLC with epidermal growth factor receptor exon20 insertions (EGFR ex20ins) are limited. Sunvozertinib is a novel orally EGFR inhibitor that has been approved to treat EGFR ex20ins NSCLC at second line setting. Herein, we reported an unexpected therapeutic outcome of first-line sunvozertinib treatment in a patient with stage IIIB EGFR ex20ins-positive lung adenocarcinoma (T1cN3M0). We found three months of sunvozertinib neoadjuvant treatment led to remarkable shrinkage of the primary tumor and downstaged N3 metastatic disease. A radical resection was scheduled after careful evaluation. Histological assessment of the resected tumor and lymph nodes showed a complete pathologic response. The patient was recommended to continue sunvozertinib as an adjuvant therapy, whereas he developed brain metastasis within three months after surgery. We proposed that the brain metastasis occurred as a result of sunvozertinib dose de-escalation-induced disease flare. Rechallenge with adequate dosage of sunvozertinib led to a rapid shrinkage of the brain metastasis. Our case highlighted the feasibility of sunvozertinib neoadjuvant therapy in EGFR ex20ins-positive NSCLC patient with locally advanced disease. Importantly, adjuvant therapy using an adequate dosage of sunvozertinib is pivotal to prevent disease flare and tumor recurrence.

Background: Systemic inflammation has emerged as a key determinant of prognosis in epithelial ovarian cancer (EOC). The pre-treatment C-reactive protein/albumin (CRP/Alb) ratio integrates host inflammatory and nutritional status, but its prognostic role in advanced-stage EOC remains incompletely defined.

Methods: We retrospectively analyzed 256 patients with FIGO stage III-IV high-grade serous ovarian cancer treated at a tertiary oncology center between 2010 and 2024. All patients underwent primary or interval cytoreductive surgery followed by standard platinum-based chemotherapy. Pre-treatment CRP and albumin values obtained within 14 days before therapy were used to calculate the CRP/Alb ratio. Patients were stratified according to the predefined median cut-off (2.32). Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. Cox regression models were applied for univariate and multivariate analyses.

Results: Median follow-up was 81.4 months. The median OS for the entire cohort was 58.1 months. Patients with a CRP/Alb ratio <2.32 had significantly longer OS (74.6 vs 45.6 months; p = 0.003) and PFS (24.8 vs 17.1 months; p = 0.026) compared to those with higher ratios. In multivariate analysis, a CRP/Alb ratio ≥2.32 remained an independent predictor of worse OS (HR = 1.88; 95% CI: 1.12-3.18; p = 0.018), along with age ≥65 years (HR = 2.34; p < 0.001) and ECOG performance status 2-3 (HR = 1.60; p = 0.006). Individual CRP or albumin levels did not retain prognostic significance.

Conclusion: The pre-treatment CRP/Alb ratio is a simple, accessible, and independent prognostic biomarker in advanced-stage EOC. Its integration into routine risk assessment may enhance individualized prognostication and help identify high-risk patients who could benefit from closer monitoring and tailored supportive care. Prospective multicenter validation is warranted.

Immune checkpoint inhibitors (ICIs) have improved outcomes in advanced non-small cell lung cancer (NSCLC) but can cause severe immune-related adverse events. We report a fatal case of suspected steroid-refractory autoimmune encephalitis in a 71-year-old male with squamous NSCLC, occurring 14 months after sequential ICI therapy (toripalimab, then sintilimab, followed by anlotinib-sintilimab). He presented with acute behavioral decline. Brain MRI revealed non-enhancing T2/FLAIR hyperintensities in the cerebellum and frontal lobes, with low cerebrospinal fluid (CSF) opening pressure. Diagnostic workup was negative for infections and neuronal autoantibodies. Despite aggressive immunosuppression with high-dose corticosteroids, mycophenolate mofetil, and intravenous immunoglobulin, his condition progressed to coma with diffuse cerebral edema and hydrocephalus, leading to death within 14 days. This case highlights the lethal potential of ICI-induced encephalitis, the diagnostic challenges of seronegative presentations, and the urgent need for more effective treatment strategies.

Background: Hepatocellular carcinoma (HCC) is a highly lethal malignancy with limited therapeutic options and poor prognosis. Identifying robust prognostic biomarkers and therapeutic targets is essential for improving patient outcomes. Minichromosome maintenance complex component 4 (MCM4), a DNA replication licensing factor, has been associated various malignancies, yet its involvement in HCC remains underexplored.

Methods: We performed integrative bioinformatics analyses on three public HCC datasets (GSE14520, GSE56545, and GSE84402) to identify consistently dysregulated genes. Functional enrichment analyses were conducted using GO, KEGG, and Reactome databases. PPI networks were constructed via STRING. The expression and prognostic value of MCM4 were evaluated using GEPIA, Human Protein Atlas, and KM-Plotter. Single-cell and spatial transcriptomics from the HCCDB were analyzed to explore MCM4 localization. Functional roles of MCM4 were validated in vitro using siRNA-mediated knockdown and plasmid-based overexpression in HepG2 and Huh7 cells.

Results: MCM4 was identified as a consistently upregulated gene in HCC and was associated with poor overall, disease-free, recurrence-free, and disease-specific survival. Single-cell and spatial transcriptomic analyses revealed MCM4 enrichment in proliferative tumor regions. Functional assays demonstrated that MCM4 promotes HCC cell growth, motility, invasiveness, and enhances EMT and stemness. Conversely, MCM4 knockdown attenuated these malignant phenotypes.

Conclusion: Our study establishes MCM4 as a key regulator of HCC progression and a potential prognostic biomarker. These findings suggest that MCM4 may serve as a potential target and underscore integrative and spatial transcriptomic approaches in cancer biomarker discovery.

Purpose: Lung adenocarcinoma (LUAD) represents the predominant histological subtype of non-small cell lung cancer (NSCLC) and is linked to a diminished overall survival (OS) rate. Icariin (ICA), the principal bioactive compound found in the medicinal plant Epimedium, has demonstrated significant efficacy in inhibiting tumor progression. Ferroptosis, an emerging mechanism of cellular demise, offers a promising avenue for therapeutic intervention in oncology. Nonetheless, the function and modulation of ferroptosis in LUAD are still significantly under-investigated.

Methods: A potential ferroptosis target was identified via bioinformatics analysis. Levels of reactive oxygen species (ROS) and ferroptosis-associated markers were quantified, while MTT, wound healing (WH), and Transwell assays were conducted to assess the effect of ICA on the malignant behavior of the LUAD cell line A549. The antitumor activity of ICA was further validated in vivo. Additionally, transcriptome sequencing and bioinformatics analysis were performed to explore ICA-induced molecular regulatory changes associated with the malignant phenotype of tumors.

Results: Bioinformatics analysis revealed that TP53 is a potential target of ferroptosis. Cellular experiments demonstrated that ICA induces ferroptosis in a dose-dependent manner, significantly reducing the proliferation, migration, and invasion abilities of A549 cells. Furthermore, the ferroptosis inhibitor Fer-1 can partially reverse both the ferroptosis and the increased expression of TP53 induced by ICA, indicating that ICA suppresses the malignant behavior of A549 cells by inducing TP53-mediated ferroptosis. This mechanism of action was further validated by in vivo experiments. Additional transcriptome sequencing and bioinformatics analysis showed that the mechanism by which ICA inhibits the proliferation of lung cancer cells may be related to its effects on cell cycle and metastasis-related gene sets, lipid metabolism, tumor immune microenvironment, and tumor-promoting pathways, including cholesterol metabolism, cortisol synthesis and secretion, and the PI3K-Akt signaling pathway.

Conclusion: ICA demonstrates antitumor properties in LUAD via TP53-mediated ferroptosis, consequently suppressing cellular proliferation.

Objective: To explore the effect of small nuclear ribonucleoprotein E (SNRPE) on proliferation and autophagy in lung adenocarcinoma (LUAD).

Methods: SNRPE expression was measured in LUAD and para-cancerous tissues by immunohistochemical detection and in LUAD cell-lines by real-time fluorescence quantitative PCR (RT-qPCR) and Western blotting. Cell proliferation was evaluated by cell counting kit (CCK-8) and colony formation, cell cycle progression and apoptosis were assessed by flow cytometry. Extracellular signal-regulated kinase (ERK)/Mammalian target of rapamycin (mTOR) signaling and autophagy proteins, Microtubule-associated protein 1 light chain 3B (LC3B), Sequestosome-1 (P62) and Beclin1 were measured by Western blotting. The impact of SNRPE expression on tumor growth in vivo was assessed by an animal model of LUAD.

Results: LUAD tissues showed high SNRPE expression and expression correlated with T stage. SNRPE knockdown in LUAD cells decreased proliferation, induced autophagy, trapped cells in G1 phase and inhibited the activation of ERK/mTOR signaling. Xenograft tumors with SNRPE knockdown showed reduced growth rate.

Conclusion: SNRPE was expressed at high levels in LUAD cancer tissues. SNRPE knockdown inhibited LUAD cell proliferation and stimulated autophagy in vivo and in vitro. SNRPE may target the ERK/mTOR signaling pathway. These findings may expose a novel target for LUAD treatment. In this study, limitations include the relatively small clinical sample size, lack of autophagy flux assays, and absence of mechanistic rescue experiments, which warrant further studies.

Colorectal cancer (CRC) is one of the most diagnosed cancers, leading to considerable cancer-related deaths globally. Recently, a notable increase has been observed in annual CRC incidence rates, particularly among individuals aged ≤50 years. Rapid urbanization and lifestyle changes have contributed to this trend. Early diagnosis through structured screening programs remains crucial for improving prognosis, yet uptake in the Gulf remains suboptimal due to limited public awareness and gaps in the national screening infrastructure. Diagnostic approaches in the region increasingly incorporate advanced imaging modalities and molecular testing, although access to in-house testing facilities is limited, often resulting in delays in personalized therapy initiation. Treatment strategies for CRC in the Gulf are guided by international guidelines, and are tailored according to tumor characteristics, molecular profile, and patient status. Multidisciplinary teams in tertiary centers facilitate evidence-based management, while ongoing efforts aim to expand access to targeted therapies and optimize care pathways. Insufficient training, limited knowledge, and suboptimal communication between primary care providers and specialists have been identified. Also, limited in-house molecular testing often leads to outsourcing, causing delays in targeted therapy and higher treatment costs. In this perspective article, we provide an overview of current practices and propose future perspectives for the screening, diagnosis, and management of CRC in the Gulf region, with the aim of aiding clinicians in making informed decisions, enhancing patient care, and establishing the cornerstone for future research.