Anti-Cancer Drugs最新文献

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive subtype of nonsmall cell lung cancer, typically occurring in elderly male smokers. Its occurrence in the adolescent population is exceptionally uncommon, with only a handful of cases reported in the literature. Even more rarely, LCNEC harbors ALK fusions, an unusual molecular alteration with important therapeutic relevance. We report a 19-year-old female patient who presented with bone pain and was found to have widespread skeletal and mediastinal lymph node involvement. Initial workup revealed elevated serum calcitonin and carcinoembryonic antigen (CEA) levels, and histopathology showed high-grade neuroendocrine carcinoma with immunoreactivity for chromogranin, synaptophysin, CD56, as well as calcitonin and CEA. Due to the neuroendocrine phenotype and calcitonin positivity, metastatic medullary thyroid carcinoma was initially suspected. However, thyroid fine needle aspiration from the suspicious thyroid nodule did not provide any evidence in this direction, and the RET mutation testing was also negative. Further molecular analysis revealed an EML4-ALK fusion and a TP53 mutation in tumor tissue. The patient was diagnosed with ALK-positive LCNEC and treated with lorlatinib and denosumab combination. A marked clinical and metabolic response was achieved within 3 months of treatment initiation. To our knowledge, this is the first reported case of ALK-rearranged pulmonary LCNEC in an adolescent patient treated with a tyrosine kinase inhibitor. This case underscores the extreme rarity of LCNEC in adolescents, highlighting that ALK rearrangements, although exceptionally rare in this histological subtype, can have significant therapeutic implications. It further emphasizes the importance of routine molecular profiling in atypical clinical scenarios and supports the utility of targeted therapies in rare tumor subsets.

Histone deacetylase 1 (HDAC1), a pivotal epigenetic modulator, is critically involved in oncogenesis and serves as a promising target for anticancer drug discovery. In this study, 59 reported HDAC1 inhibitors were utilized to establish robust three-dimensional quantitative structure-activity relationship models for designing novel triazole-containing derivatives with optimized bioactivity and pharmacokinetic profiles. Comparative molecular field analysis ( n  = 9, R2  = 0.966, q2  = 0.781) and comparative molecular similarity index analysis ( n  = 6, R2  = 0.945; q2  = 0.778) confirmed the predictive reliability of these models. On the basis of the contour maps analysis, the key structural modification sites were determined, and seven promising analogs were reasonably designed. These candidates showed good drug-likeness in ADME/T profiling and formed stable complexes with HDAC1 in molecular simulations, underscoring their promising inhibitory potential. Our study provided a strategic framework for the discovery of HDAC1 drugs and identified promising leads for cancer therapeutics.

Viral oncogenes E6 and E7 are ideal targets for therapeutic vaccines against human papillomavirus (HPV)-associated cervical cancer (CC). T cell-mediated immunity plays a crucial role in the clearance of HPV infection and regression of intraepithelial neoplasia. Current strategies for therapeutic vaccine development predominantly depend on immunoinformatic predictions of human leukocyte antigen (HLA)-restricted cytotoxic T lymphocyte (CTL) epitopes. Three T-cell epitope prediction programs were used to identify HPV16 E6 and E7 epitopes restricted to HLA-A*02:01. Subsequently, in silico evaluations were performed using five bioinformatic databases and computational servers. The binding affinities of these peptides to HLA-A2 molecules were experimentally validated using a T2 cell-binding assay. The effectiveness of the vaccine developed by combining peptides and CpG-containing oligonucleotide (CpG-ODN) was validated by inducing the generation of CTLs ex vivo, and its immunogenicity was verified in HLA-A*02:01/H-2D d (AAD) transgenic mice. Eight HLA-A*02:01-restricted candidate peptides were preliminarily identified, and all candidate peptides demonstrated binding capabilities to HLA-A2 molecules. Using the integrated approach, four high-affinity peptides were successfully identified. Notably, these peptides also exhibited the potential to induce dendritic cell maturation, enhance the activation and proliferation of CD8 + T cells, and elicit potent antigen-specific CTL responses against tumor cells. These findings support the potential application of the selected peptides in CTL-based immunotherapy for HPV-driven malignancies. Furthermore, the described peptide-screening platform proved to be an effective strategy for the rational design of candidate antigens for HPV therapeutic vaccines.

Oxaliplatin resistance remains a critical barrier to effective colorectal cancer treatment. The molecular mechanisms underlying this resistance are not fully understood, highlighting the need to define the transcriptional alterations that contribute to therapeutic failure. Accordingly, a comparative transcriptome analysis was performed on oxaliplatin-resistant colorectal cancer cells (HCT-116-ROx) and their parental counterparts (HCT-116) using RNA sequencing in this study. Differentially expressed gene (DEG) analysis was conducted using a quasi-likelihood negative binomial model. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were carried out using the topGO and clusterProfiler packages, respectively. To confirm the robustness of the transcriptomic data, the genes with the most significant expression changes, based on false discovery rate-adjusted P value less than 0.05 and a |logFC| > 2 thresholds, were selected for validation by quantitative real-time PCR (qRT-PCR). A total of 313 DEGs were identified, including ALDH3A1 and TACSTD2 (upregulated) and IFITM1 (downregulated); these three genes were chosen for validation by qRT-PCR. Gene Ontology enrichment revealed significant changes in cell motility, redox regulation, and extracellular matrix remodeling. KEGG analysis indicated upregulation of ferroptosis, glutathione metabolism, and lysosome-related pathways, and downregulation of p53 signaling, oxidative phosphorylation, and cancer-specific pathways. Oxaliplatin-resistant colorectal cancer cells undergo multifaceted transcriptional reprogramming that promotes redox homeostasis, metabolic adaptation, and structural plasticity while suppressing apoptotic and mitochondrial functions. These changes support chemoresistance and may represent potential therapeutic targets to restore drug sensitivity.

Bladder cancer (BLCA) is a highly aggressive malignancy, with chemotherapy resistance being a significant factor in treatment failure. In the tumor microenvironment, M2 macrophage polarization is essential for immune suppression and treatment resistance. Key genes linked to M2 macrophage polarization and gemcitabine resistance in BLCA are examined in this work, along with possible underlying processes. Bioinformatics analyses were performed to identify differentially expressed genes in BLCA. Key hub genes related to M2 macrophage polarization and gemcitabine resistance were identified using various bioinformatics tools, including Cibersort, weighted gene coexpression network analysis, and gene set enrichment analysis. The effects of prostate transmembrane androgen inducible protein 1 (PMEPA1) silencing on cell viability, gemcitabine resistance, and macrophage polarization were further assessed using reverse transcription-quantitative PCR, Western blot, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, ELISA, and flow cytometry. Bioinformatics analysis revealed that PMEPA1 is a core gene associated with M2 macrophage polarization and gemcitabine resistance. Knockdown of PMEPA1 in BLCA cell lines reduced cell viability and enhanced gemcitabine sensitivity. Silencing of PMEPA1 also promoted M1 macrophage polarization while decreasing M2 macrophage polarization, as shown by the downregulation of cluster of differentiation (CD) 163 + and upregulation of CD86 + . Mechanistically, PMEPA1 regulated the P38-mitogen-activated protein kinase (MAPK)/C-C motif chemokine ligand 2 (CCL2) axis, leading to M2 macrophage polarization. Our findings suggest that PMEPA1 plays a crucial role in regulating M2 macrophage polarization and gemcitabine resistance in BLCA by activating the P38-MAPK/CCL2 signaling pathway.

Ubiquitylation plays a crucial role in posttranslational modification, and its dysregulation is linked to chemosensitivity. However, its role in oxaliplatin (OXA) resistance in colorectal cancer (CRC) remains unclear. Transcriptomic data from the cancer genome atlas (TCGA) and Gene Expression Omnibus were used to develop a ubiquitylation-OXA resistance-related risk score (URGScore), integrating immunological, mutational, and clinical features. Single-cell RNA sequencing (scRNA-seq) identified OXA-resistant cell populations, and Genomics of Drug Sensitivity in Cancer predicted drug sensitivity. GSVA analyzed enriched pathways. Ubiquitin-specific protease 7 (USP7) expression and function were validated in CRC. A 10-gene OXA resistance signature effectively classified CRC patients into OXA-sensitive or -resistant groups. Low-URGScore patients showed greater benefit from immunotherapy. scRNA-seq highlighted the MK signaling pathway, particularly in dendritic cells and progenitors, with NCL as a key MK receptor directly interacting with USP7. Potential drugs for high-risk patients were identified. Functionally, USP7 promoted CRC proliferation, invasion, and OXA resistance in vitro. We generated an ubiquitylation-OXA-resistant CRC risk model that was employed to provide potential therapeutic targets and strategies for treating CRC patients exhibiting OXA-resistance.

Cisplatin resistance remains a major challenge in laryngeal squamous cell carcinoma (LSCC) treatment. Aldehyde dehydrogenase 9A1 (ALDH9A1), a mitochondrial matrix protein, is dysregulated in various cancers, but its role in LSCC is unclear. This study demonstrates that ALDH9A1 is significantly downregulated in LSCC tissues, and low ALDH9A1 expression correlates with poor patient prognosis. Functionally, ALDH9A1 overexpression inhibits LSCC cell proliferation, migration, and invasion while promoting apoptosis. Mechanistically, ALDH9A1 interacts with and stabilizes PTEN-induced kinase 1 (PINK1), leading to activation of PINK1-Parkin-mediated mitophagy. Under cisplatin treatment, ALDH9A1 is upregulated and induces protective mitophagy, contributing to cisplatin resistance. Inhibition of mitophagy with chloroquine sensitizes LSCC cells to cisplatin. These findings identify ALDH9A1 as a key regulator of mitophagy and cisplatin resistance in LSCC, suggesting that targeting the ALDH9A1/PINK1 axis could provide a novel therapeutic strategy for overcoming cisplatin resistance.

This study aimed to explore the clinical significance and potential mechanisms of the transforming growth factor- β1 (TGF-β1)/small mother against decapentaplegic (SMAD) and nuclear factor kappa B (NF-κB) pathways in colorectal cancer (CRC). Transcriptomic and clinical data of CRC patients were retrieved from TCGA and GEO databases, analyzed via TCGAbiolinks, GEPIA 2, KEGG, and GO. A total of 275 colon cancer and 92 rectal cancer samples were included. Results showed TβR2 and SMAD2 expression was significantly associated with CRC pathological stage ( P  < 0.05), while low TGF-β1, TβR1, and TβR2 expression correlated with longer disease-free survival (DFS, P  < 0.05). Pathway component correlations differed between normal and cancerous tissues; high co-expression of NF-κB1 and SMAD2 linked to longer DFS in rectal cancer ( P  < 0.05). Signal transducer and activator of transcription 3 (STAT3) strongly correlated with NF-κB1, SMAD2/4 (R = 0.7, 0.63, 0.65; P  < 0.001), and combinations of NF-κB1 with SMAD2/SMAD4 showed strong correlations with STAT3 (R = 0.73; P  < 0.001). NF-κB1 combined with SMAD2 has prognostic value for rectal cancer, and STAT3 may be a common upstream transcription factor regulating both pathways.

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are among the most common oncogenic drivers in human cancer and are associated with poor prognosis, limited therapeutic options, and frequent resistance to standard treatments. The approval of the first direct KRAS G12C inhibitors demonstrated that mutant KRAS can be targeted clinically, but their efficacy is restricted to a narrow allelic subset and is limited by adaptive resistance. This review summarizes recent advances in KRAS-targeted drug development beyond G12C and outlines emerging strategies designed to improve therapeutic outcomes. A comprehensive literature review was conducted using preclinical and clinical data from studies investigating KRAS inhibitors, rat sarcoma (RAS) pathway modulators, and rational drug combinations. Particular attention was given to allele-specific agents, pan-RAS inhibitors, feedback signaling mechanisms, and resistance biology. Next-generation KRAS inhibitors targeting non-G12C alleles, including KRAS G12D selective agents, have demonstrated potent preclinical activity but remain susceptible to feedback mitogen-activated protein kinase (MAPK) reactivation. Pan-RAS inhibitors that bind the active RAS-GTP state show activity across multiple alleles and tumor types, although toxicity and therapeutic window remain key concerns. Indirect strategies targeting SHP2, SOS1, and downstream MAPK components enhance pathway suppression and delay resistance, especially in combination with direct KRAS inhibitors. Resistance mechanisms encompass secondary KRAS mutations, bypass signaling through alternative RAS isoforms, and activation of parallel pathways. Comutations such as STK11 or KEAP1 further influence therapeutic response and immune contexture. KRAS-directed therapy is rapidly expanding beyond G12C, with allele-specific inhibitors, pan-RAS approaches, and rational combinations offering new opportunities for broader clinical benefit. Ongoing challenges include toxicity management, resistance evolution, and the development of predictive biomarkers to guide therapy selection.

Tumor-associated macrophages, predominant immunosuppressive components within the tumor microenvironment, critically regulate lung adenocarcinoma (LUAD) progression; however, their molecular regulatory mechanisms remain incompletely characterized. The Cancer Genome Atlas database analysis revealed absent in melanoma 2 (AIM2) expression in LUAD. The correlation between AIM2 expression and M2 macrophage infiltration levels was further evaluated. Putative transcriptional regulators upstream of AIM2 were predicted through bioinformatics screening, with JASPAR employed to identify potential binding sites between candidate factors and the AIM2 promoter. These predictions were experimentally validated using dual-luciferase reporter assays. Furthermore, we established a LUAD cell-macrophage coculture system. We performed flow cytometric analysis of macrophage surface CD206 expression, quantitative PCR quantification of mRNA levels, ELISA quantification of cytokine secretion profiles, and Western blot detection of proteins. Bioinformatics analysis revealed that AIM2 was highly expressed in LUAD tumor tissues and positively correlated with the marker genes of M2 macrophages. Overexpression of AIM2 in LUAD cells promoted the expression of CD206 on the macrophage surface, upregulated the mRNA expression levels of M2 macrophage marker genes such as CD163, ARG1, and MRC1, and enhanced the secretion of transforming growth factor-beta and interleukin-10 . These results indicated an increased level of macrophage polarization towards the M2 phenotype, and inhibiting the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway reversed the above phenomenon. Furthermore, the interferon regulatory factor 4 (IRF4) promoted the transcription of AIM2. IRF4 knockdown in LUAD cells suppressed M2 macrophage polarization, but simultaneous overexpression of AIM2 restored it to baseline levels. IRF4 drives M2 macrophage polarization in LUAD via the AIM2-mediated PI3K/AKT signaling pathway.