Anti-programmed cell death protein 1 (anti-PD-1) immunotherapy has shown efficacy in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), but current biomarkers have limitations in predicting immunotherapy response accurately. Chromosome 11q13 amplification, prevalent in HNSCC, has been associated with reduced efficacy of anti-PD-1 therapy. This study aims to prospectively evaluate 11q13 amplification as a biomarker for guiding first-line treatment in R/M HNSCC. We hypothesize that excluding patients with 11q13 amplification from anti-PD-1 therapy may enhance survival outcomes.

Metastasis-associated protein 2 (MTA2), a master transcriptional regulator, through multiple target genes and interacting proteins, has been demonstrated to play a vital role in the regulation of proliferation, replication, apoptosis, autophagy, DNA damage repair, preimplantation, embryonic development and immune cell differentiation. Despite extensive research, the physiological role and pathogenic mechanisms of MTA2 remain poorly understood. Here, we mainly review in the current research the status of MTA2 and its implications in normal development and various tumor biology. Accumulating evidence suggests that MTA2 is frequently amplify in several types of cancers, closely associates with tumor cells migration and invasion, relates to the malignant characteristics and poor prognosis, which therefore has been considered as playing tumor oncogenic roles. Substantial evidence indicates that MTA2 functions by modulating downstream targets including cell growth, invasion as well as angiogenesis related genes. Confusingly, the proliferation effect of MTA2 remains elusive and even conflicting in the development of several solid tumors. Furthermore, we discuss the upstream regulation of MTA2 by transcription factors, microRNAs and lncRNAs in specific physiology and pathology conditions, which results in the abnormal MTA2 expression in various aspects of cancer. In this context, we summarize linked function of MTA2 directly to oncogenesis and might provide a significant avenue for the treatment of diseases. We hope that this review will help tumor molecular biologists further understand the molecular mechanism of MTA2 in normal development and cancer.

Breast cancer (BC) is the most common cancer affecting women worldwide. There is a strong need to identify molecular pathways that might represent effective therapeutic targets.

Gene therapy introduces therapeutic genes into cancer cells to inhibit tumor growth or induce apoptosis. The htsFLT01 gene, a novel anti-angiogenic construct, encodes the sFLT01 protein that functions as a Vascular Endothelial Growth Factor (VEGF) decoy receptor, impeding pathological angiogenesis. When combined with the MiRGD nanocarrier-a versatile peptide-based delivery system optimized for specificity, biocompatibility, and low toxicity-the htsFLT01/MiRGD complex offers a potent strategy against breast cancer.

Emerging evidence highlights the pivotal involvement of microRNAs (miRNAs) in modulating epithelial-mesenchymal transition (EMT) processes during gastric carcinogenesis. The present study specifically explored the functional significance of miR-384 and its molecular mechanisms in gastric cancer (GC) progression. Comparative analysis of miR-384 expression profiles between GC specimens and adjacent normal tissues was performed using RT-qPCR. Functional characterization was achieved through gain-of-function and loss-of-function approaches by transfecting GC cells with miR-384 mimics or inhibitors, followed by evaluation of proliferative capacity, invasive potential and EMT markers. Potential mRNA targets were predicted via bioinformatics algorithms, with subsequent validation through rescue experiments demonstrating miR-384's direct binding to CTNNB1. Complementary in vivo studies were conducted to assess the tumor-suppressive effects of miR-384. A marked reduction in miR-384 expression was observed in both clinical GC samples and cultured cell lines relative to normal counterparts. Ectopic miR-384 expression significantly attenuated malignant phenotypes, suppressing cellular proliferation and motility while inducing apoptotic pathways. Computational prediction coupled with experimental verification identified CTNNB1 as a direct downstream target, through which miR-384 exerts its inhibitory effects on nuclear translocation and subsequent modulation of EMT and proliferative pathways. Importantly, the miR-384/CTNNB1 axis was shown to effectively constrain tumor growth in animal models. miR-384 exerts tumor-suppressive effects in GC by inhibiting cellular proliferation and EMT, while promoting apoptosis through downregulation of CTNNB1.

The v-Raf murine sarcoma viral oncogene homolog B (BRAF) gene is one of the most critical proto-oncogenes and functions as a key regulator in the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway. The incidence of BRAF mutations in non-small cell lung cancer (NSCLC) patients ranges from 1.5% to 5.5%, with BRAF V600 mutations accounting for approximately 30%-50% of all BRAF mutations, among which BRAF V600E represents the most prevalent mutation type. Currently, the combination of Dabrafenib and Trametinib has been recommended as first-line therapy for BRAF V600-mutant NSCLC by multiple domestic and international guidelines including National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO), and Chinese Society of Clinical Oncology (CSCO). However, there are no clear targeted treatment recommendations for BRAF non-V600 mutations. Although case reports suggest that Dabrafenib combined with Trametinib may be effective for patients with BRAF non-V600 mutations, the efficacy and safety require further validation due to limited sample size and lack of large-scale clinical trial data. This article reports a case of NSCLC with a rare BRAF insertion and deletion mutation that responded well to the treatment of Dabrafenib in combination with Trametinib, aiming to enhance clinicians' understanding of such NSCLC cases with extremely rare mutation and provide a reference for future treatment strategies.
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Human epidermal growth factor receptor 2 (HER2) mutations play a role as a driver gene in non-small cell lung cancer (NSCLC). Patients with advanced NSCLC harboring HER2 mutations exhibit poor responses to conventional chemotherapy and immunotherapy, hence targeted therapies against HER2 are under extensive investigation. This review analyzes the biological characteristics of HER2, an overview of clinical trials for targeted therapy drugs, including monoclonal antibodies, tyrosine kinase inhibitors (TKIs), and antibody-drug conjugate, and research directions for drug resistance in NSCLC. Currently, Pyrotinib and Trastuzumab deruxtecan have been approved for the treatment of advanced NSCLC with HER2 mutations, suitable for patients who have failed standard therapy, which is far from meeting the clinical demands. Novel selective HER2 TKIs are gradually emerging. Future exploration trends are gradually shifting from single drugs to combination strategies, and are exploring more precise selection strategies as well as research on resistance mechanisms. These studies will provide a theoretical basis for clinical treatment strategies for advanced NSCLC with HER2 mutations, promoting the development of personalized therapy.
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Lung cancer stands as the primary cause of cancer-related mortalities globally, presenting a severe menace to human health. In individuals with non-small cell lung cancer (NSCLC), Kirsten rat sarcoma viral oncogene (KRAS) mutations serve as crucial oncogenic drivers. NSCLC with KRASG12C mutation is among the most prevalent subtypes. Currently, the detection methods for KRAS mutations predominantly concentrate on polymerase chain reaction (PCR) and sequencing platforms. The diverse derivative technologies of these two platforms each exhibit distinct merits and demerits in terms of testing performance and detection throughput, and find significant applications in tissue biopsy and liquid biopsy. In targeted therapies, KRASG12C targeted drugs, including Sotorasib, Adagrasib, Fulzerasib, Garsorasib, and Glecirasib, have demonstrated certain therapeutic efficacies in clinical trials and have obtained marketing approval. To tackle drug resistance and enhance patient's prognoses, combination therapeutic strategies that integrate targeted agents with chemotherapy, immune checkpoint inhibitors, Src homology region 2 domain-containing phosphatase 2 (SHP2) inhibitors, and epidermal growth factor receptor (EGFR) monoclonal antibodies have emerged. This paper systematically reviews the advancements in the diagnosis and targeted therapy of NSCLC with KRASG12C mutation, aiming to offer a reference for the selection of clinical treatment regimens and subsequent research.
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The incidence of leptomeningeal metastasis (LM) in patients with advanced non-small cell lung cancer (NSCLC) is increasing gradually. However, it poses therapeutic challenges due to limited effective interventions. Intrathecal Pemetrexed (IP) holds broad application prospects in the therapeutic domain of LM. This study aims to evaluate the efficacy, safety, and optimal combination strategies of IP in NSCLC-LM patients with epidermal growth factor receptor (EGFR) mutation-positive status, with the aim of providing real-world data support for exploring more precise personalized treatment strategies for these patients.

RSK plays a central role in oncogenic signaling, yet its broader regulatory impact in esophageal squamous cell carcinoma (ESCC) remains unclear. We performed integrated phosphoproteomics and kinase-substrate network analysis to elucidate global signaling alterations following RSK inhibition in ESCC cells. In Eca-109 cells, treatment with a moderate concentration of the selective RSK inhibitor SL0101 effectively suppressed proliferation without inducing apoptosis. To elucidate potential compensatory survival mechanisms, we performed integrated proteomic and phosphoproteomic analyses, which revealed that RSK inhibition provokes broad cellular adaptations. Importantly, the magnitude of these effects varied across pathways. Ribosome biogenesis and mitochondrial organization exhibited substantial perturbation primarily at the proteomic level, reflecting system-level dysregulation. Phosphoproteomic analysis revealed that large-magnitude alterations in nuclear transport and mRNA processing, and more subtle, fine-tuned modulation of mitotic fidelity. Kinase activity inference further identified MAPK14, CDK2, SRPK3, AKT1, PLK1, and PIM2 as principal regulators that may regulate compensatory signaling in response to RSK suppression. Taken together, our study reveals that RSK inhibition reprograms kinase networks to enforce stress adaptation, maintaining oncogenic homeostasis despite perturbations. These findings highlight a potential therapeutic window for early intervention strategies, suggesting that combination strategies may enhance the efficacy of RSK-directed therapies in ESCC.

Human papillomavirus (HPV) infection is a primary driver of cervical cancer. Integration of HPV into the human genome causes persistent expression of viral oncogenes E6 and E7, which promote carcinogenesis and disrupt host genomic function. However, the impact of integration on host gene expression remains incompletely understood. We used multimodal RNA sequencing, combining total RNA-seq and Cap Analysis of Gene Expression (CAGE), to clarify virus-host interactions after HPV integration. HPV-derived transcripts were detected in 17 of 20 clinical samples. In most specimens, transcriptional start sites (TSSs) showed predominant early promoter usage, and transcript patterns differed with detectable E4 RNA region. Notably, the high RNA expressions of E4 region and viral-human chimeric RNAs were mutually exclusive. Chimeric RNAs were identified in 13 of 17 samples, revealing 16 viral integration sites (ISs). CAGE data revealed two patterns of TSS upregulation centered on the ISs: a two-sided pattern (43.8%) and a one-sided pattern (31.3%). Total RNA-seq showed upregulation of 12 putative cancer-related genes near ISs, including MAGI1-AS1, HAS3, CASC8, BIRC2, and MMP12. These findings indicate that HPV integration drives transcriptional activation near ISs, enhancing expression of adjacent oncogenes. Our study deepens understanding of HPV-induced carcinogenesis and informs precision medicine strategies for cervical cancer.

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia driven by the PML/RARα fusion protein. Standard treatment with all-trans retinoic acid (ATRA) combined with chemotherapy is effective, but resistance and adverse effects remain significant challenges. Melittin, the primary peptide component of bee venom, has demonstrated potent anticancer activity across multiple leukemia subtypes through mitochondrial-dependent mechanisms. Building upon this established evidence, we investigated melittin's therapeutic potential in APL to address the specific clinical challenge of ATRA resistance.

N6-methyladenosine (m6A) modifications are among the most prevalent epigenetic marks in eukaryotic RNAs, regulating both coding and non-coding RNAs and playing a pivotal role in RNA metabolism. Given their widespread influence, m6A modifications are deeply implicated in the pathogenesis of various cancers, including highly aggressive malignancies such as lung cancer, melanoma, and liver cancer. Dysregulation of m6A dynamics-marked by an imbalance in methylation and demethylation-can drive tumor progression, enhance metastatic potential, increase aggressiveness, and promote drug resistance, while also exerting context-dependent tumor-suppressive effects. Given this dual role, precise modulation of m6A levels and the activity of its regulatory enzymes (writers, erasers, and readers) represent a promising therapeutic avenue. In this review, we highlight recent advances in targeting m6A machinery, including small-molecule inhibitors, antisense oligonucleotides, and CRISPR/Cas-based editing tools, capable of both writing and erasing m6A marks and altering m6A methylation sites per se. By evaluating these strategies, we aim to identify the most effective approaches for restoring physiological m6A homeostasis or for strategically manipulating the m6A machinery for therapeutic benefit.

Protein homeostasis is a dynamic process essential for cellular function and survival, tightly controlled by the ubiquitin-proteasome system. Within this system, ubiquitin-specific protease 7 (USP7) plays a key role as a deubiquitinating enzyme, thus modulating the stability, localization, and activity of a wide variety of substrates. USP7 is involved in critical cellular processes such as DNA repair, apoptosis, immune response, and epigenetic regulation. The dysregulation of USP7 expressions or activity has been linked to several pathological conditions, including cancer, neurodegenerative and inflammatory diseases, and viral infections. This enzyme exerts its biological functions through the stabilization of both oncogenic and tumor suppressor proteins, highlighting its sensitive role in tumorigenesis. Despite the identification of selective USP7 inhibitors with promising preclinical activity, the development of clinically effective compounds remains a major challenge. This review summarizes the current understanding of USP7 structure, function, and biological relevance, with a particular emphasis on its potential as a therapeutic target in oncology.

Background and Objectives: Erlotinib, a tyrosine kinase inhibitor (TKI), is an established therapy for patients with metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Preclinical and clinical evidence suggests that chronic stress, mediated through β-adrenergic signaling, promotes tumor progression, angiogenesis, and therapy resistance. Furthermore, interactions between β-adrenergic signaling and EGFR pathways have been hypothesized to negatively influence treatment responses. Based on this rationale, we investigated whether concomitant beta-blocker use may improve survival outcomes in EGFR-mutant NSCLC patients treated with erlotinib. Materials and Methods: This retrospective analysis included 103 patients with metastatic EGFR-mutant NSCLC who received erlotinib. Patients were classified according to concurrent beta-blocker use, defined as continuous therapy for at least six months prior to erlotinib initiation, prescribed for cardiovascular indications. Progression-free survival (PFS) and overall survival (OS) were compared between beta-blocker users and non-users. Results: Patients receiving erlotinib with concomitant beta-blocker therapy achieved a median PFS (mPFS) of 21.4 months (95% CI, 13.1-29.7), compared with 9.7 months (95% CI, 6.7-12.7) in non-users (p = 0.003). Median OS (mOS) was 32.4 months (95% CI, 14.8-50.0) in the beta-blocker group versus 19.9 months (95% CI, 14.8-25.0) in the non-beta-blocker group (p = 0.010). Multivariate Cox regression confirmed beta-blocker use as an independent prognostic factor for both PFS (p = 0.004) and OS (p = 0.014). Conclusions: Concomitant beta-blocker use was associated with significantly prolonged survival in patients with EGFR-mutant metastatic NSCLC receiving erlotinib. These findings support the hypothesis that β-adrenergic inhibition enhances the efficacy of EGFR-targeted therapy. Prospective studies are warranted to validate these results and to further elucidate the underlying biological mechanisms.

Background and Objectives: Breast cancer (BC) is a complex disease requiring a comprehensive treatment approach due to its diverse characteristics. Critical molecular determinants of BC have been identified using advanced genomic, transcriptomic, and proteomic approaches. Assessing the biomarkers associated with the onset of early-stage BC may help identify the risk of metastasis and inform treatment decisions. A previous bioinformatic analysis using two large BC cohorts identified pumilio RNA binding family member 1 (PUM1) as a key gene in invasive BC. However, no study has yet examined the prognostic and predictive value of PUM1 in invasive BC and its correlation with aggressive tumor behavior. This study aimed to fill this need. Materials and Methods: Correlations between PUM1 expression and patients' clinicopathological characteristics and outcomes were explored in publicly available BC transcriptomic data acquired using DNA microarrays (n = 10,872) and RNA sequencing (n = 4421) using BC Gene-Expression Miner v5.0. PUM1 expression in samples from 100 patients with invasive BC at King Abdul Aziz Specialist Hospital, Saudi Arabia, was assessed immunohistochemically. Correlations between PUM1 expression and patients' clinicopathological characteristics (e.g., age, tumor grade, tumor size, and outcome) were assessed. The online platform ROC Plotter was also used to investigate the predictive significance of PUM1. Results: High PUM1 gene and protein expression correlated positively with aggressive features of BC, including high histological grade, high Ki-67 expression, negative hormone receptors, and the triple-negative BC molecular subtype. High PUM1 expression correlated with poor outcomes, and high PUM1 expression was associated with a lower pathological complete response to anti-endocrine treatment but a high response to chemotherapy. Conclusions: These results indicate that PUM1 may serve as a potential prognostic and predictive biomarker in patients with invasive BC. PUM1 may serve as a therapeutic target in BC cases with unfavorable prognoses. However, further validation in larger, multi-center cohorts and further functional assessment are required to deepen our understanding of PUM1's role in BC.

Background and Objectives: Urothelial carcinoma of the urinary bladder is a heterogeneous disease with diverse morphological and molecular characteristics. This study aims to analyze the expression of HER2 in 100 consecutive cases of muscle-invasive bladder carcinoma (MIBC), with a special attention to the different histological subtypes and consensus molecular variants determined by IHC methods. Materials and Methods: A retrospective single-center study was conducted on 100 consecutive cases of MIBC (2021-2024). HER2 status is assessed by immunohistochemistry (IHC) (scores 0, 0+, 1+, 2+, 3+), and the results are compared with the published data. Results: We have established that over half of the tumors (~60%) show some level of HER2 expression, with strong expression (3+) present in 25%. There are significant differences among the IHC-based molecular variants: luminal tumors, including papillary tumors, exhibit a frequent HER2 overexpression, whereas those with a basal immunophenotype (e.g., squamous, sarcomatoid variants) are almost entirely HER2-negative. The micropapillary subtype and some other rare subtypes can also express HER2. Conclusions: HER2 is an important biomarker with heterogeneous expression in urothelial carcinoma of the bladder. The present study showed that the frequency and level of HER2 expression vary substantially among different histopathological subtypes and molecular variants. In therapeutic terms, interest in HER2 as a target is growing-new antibody-drug conjugates show a promising activity even in cases with low HER2 expression, which will likely lead to the integration of HER2-directed therapies and routine testing in the future.

High-grade serous carcinoma (HGSC) of the ovary is characterized by two major histological patterns: a classic papillary/micropapillary architecture and a solid pseudo-endometrioid transitional (SET) variant. We investigated whether the distinct morphologic subtypes are underpinned by transcriptomic differences in the tumor microenvironment (TME). We profiled 21 HGSC tumors (7 SET, 14 classic) using a 770-gene NanoString PanCancer Progression panel. Differential expression analysis revealed ~20 genes with significantly different expression (>4-fold, adjusted p < 0.01) between SET and classic tumors. Unsupervised clustering partially separated SET and classic tumors, suggesting that global gene expression patterns correlate with histologic subtype. SET tumors exhibited upregulation of cell-cycle and epithelial genes (e.g., PTTG1, TRAIL, HER3) and downregulation of genes involved in epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) organization, and angiogenesis (e.g., TWIST2, FGF2, decorin) relative to classic tumors. Notably, PTTG1 and TRAIL were upregulated ~6-9-fold in SET tumors, whereas TWIST2 was ~7-fold downregulated, consistent with reduced EMT in SET tumors. Pathway analysis indicated that SET tumors appear to have an immune-active, stroma-poor microenvironment, in line with an "immunoreactive" phenotype, whereas classic tumors showed a mesenchymal, stroma-rich profile. These molecular distinctions could have diagnostic utility and may inform therapeutic stratification, with key dysregulated genes (e.g., HER3, TRAIL, FGF2) representing potential prognostic or predictive biomarkers. For example, high HER3 expression in SET tumors might predict sensitivity to ERBB3/PI3K inhibitors, whereas stromal factors (e.g., FGF2) enriched in classic HGSC could be targeted with microenvironment-modulating therapies. These preliminary findings require validation before translation into pathology practice via immunohistochemical (IHC) assays (e.g., for HER3 or TRAIL), potentially enabling improved classification and personalized treatment of HGSC. We report effect sizes as log2 fold change with 95% confidence intervals and emphasize FDR-adjusted q-values. Given the small sample size and the absence of outcome data (OS/PFS/PFI), results are preliminary and hypothesis-generating. Orthogonal protein-level validation and replication in larger, independent cohorts are required before any translational inference.

Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of kidney cancer. This study aimed to construct a prognostic model for ccRCC based on glycosyltransferase genes, which play important roles in cell processes like proliferation, apoptosis. Glycosyltransferase genes were collected from four public databases and analyzed using RNA-seq data with clinical information from three ccRCC datasets. Prognostic models were constructed using eight machine learning algorithms, generating a total of 117 combinatorial algorithm models, and the StepCox[forward]+Ridge model with the highest predictive accuracy (C-index = 0.753) which selected and named the Glycosyltransferases Risk Score (GTRS) model. The GTRS effectively stratified patients into high- and low-risk groups with significantly different overall survival and maintained robust performance across TCGA, CPTAC, and E-MTAB1980 cohorts (AUC > 0.75). High-risk patients exhibited higher tumor mutational burden, immunosuppressive microenvironment, and poorer response to immunotherapy. TYMP and GCNT4 were experimentally validated as key genes, functioning as oncogenic and tumor-suppressive factors. In conclusion, GTRS serves as a reliable prognostic tool for ccRCC and provides mechanistic insights into glycosylation-related tumor progression.

Pheochromocytomas and paragangliomas (PPGL) are classified as rare cancers but can be highly metastatic, particularly in individuals with inherited succinate dehydrogenase B (SDHB) mutations. As current therapies and the availability of SDHB-deficient animal models are both limited, we have previously constructed a nematode PPGL model, a transgenic worm carrying the R244H missense mutation equivalent to human R230H in the sdhb-1 gene. In this study, we show that R244H mutants display characteristics of PPGL tumors, such as pseudohypoxia activation and the accumulation of reactive oxygen species. The latter can be the result of compromised antioxidant machinery, as R244H mutants have reduced levels of cytosolic and mitochondrial superoxide dismutase enzymes. In addition, the expression of mitophagy markers pink-1 (PTEN-induced putative kinase) and pdr-1 (E3 ubiquitin-protein ligase parkin) were downregulated in R244H mutants, suggesting impaired mitophagy and reflecting the crucial role of mitochondrial health in PPGL pathology. Treatments by the SDH inhibitor fluopyram revealed that the SDH complex carrying the R244H mutation in subunit B displayed residual SDH activity, which was also confirmed by our structural analyses. We also observed a link between dopaminergic neuronal health and SDHB-1.