Current cancer drug targets最新文献

{"title":"CircRNAs Crosstalk with Key Signaling Proteins in the Progression of Hepatocellular Carcinoma.","authors":"Haoyun Deng, Zhizhong Xie, Guotao Tang, Jia Yu, Shengsong Tang, Xiaoyong Lei, Xiaoyan Yang","doi":"10.2174/0115680096453582260325053128","DOIUrl":"https://doi.org/10.2174/0115680096453582260325053128","url":null,"abstract":"<p><p>Hepatocellular Carcinoma (HCC) represents one of the most prevalent and lethal malignancies worldwide, posing a significant global health challenge with increasing incidence and poor prognosis. Aberrant expression of circular RNAs (circRNAs) has emerged as a critical factor in HCC pathogenesis, positioning them as promising biomarkers and novel therapeutic targets. CircRNAs exert profound influence on diverse cellular processes by interacting with key signaling pathways essential for cell proliferation, immune evasion, and metabolic homeostasis. Their functional roles encompass promoting cancer cell growth, metastasis, invasion, Epithelial-Mesenchymal Transition (EMT), metabolic reprogramming, and tumor angiogenesis, as depicted in Fig. (1). A central focus of this review is deciphering the mechanistic interplay between circRNAs and these pathways, including the Wnt/βcatenin, PI3K/Akt, and MAPK pathways. CircRNAs dynamically regulate gene expression by acting as competing endogenous RNAs (ceRNAs) that sponge microRNAs (miRNAs) to modulate messenger RNA (mRNA) stability and translation-reflecting the current predominance of ceRNA-focused studies in the field-while direct protein interactions and correlative expression with signaling pathways represent less explored but critical modes of crosstalk. This interaction forms intricate molecular networks that critically govern HCC progression, as outlined in Fig. (2). Specific examples, such as the tumor-suppressive circMTO1 (inhibits proliferation via miR-195-5p) and circZKSCAN1 (which inhibits HCC progression through multiple signaling pathways and enhances sorafenib sensitivity), illustrate the critical tumor-suppressive roles of circRNAs in HCC. While challenges remain in clinical application, including standardization of detection methods and delivery systems for therapy, the potential for circRNA-based diagnostics and therapeutics is significant, though still in the preclinical stage. The exploration of circular RNAs (circRNAs) in liquid biopsies presents a promising avenue for early detection and personalized medicine. This review comprehensively summarizes the current understanding of circRNAs in HCC, covering their roles in disease initiation and progression, their prognostic value, and their emerging potential as both non-invasive biomarkers and targeted therapeutic agents.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resistance Mechanisms of Alectinib in ALK-Positive Non-Small Cell Lung Cancer and Therapeutic Strategies.","authors":"Yanru Zhao, Chang He, Juanjuan Xiao, Yafei Zheng, Feng Zhu, Qiuhong Duan, Shuang Zhao","doi":"10.2174/0115680096432322260407112955","DOIUrl":"https://doi.org/10.2174/0115680096432322260407112955","url":null,"abstract":"<p><p>Anaplastic Lymphoma Kinase (ALK) -positive Non-Small Cell Lung Cancer (NSCLC) treatment has advanced dramatically since the EML4-ALK fusion gene discovery. Alectinib, a first-line ALK-Tyrosine Kinase Inhibitor (TKI) with high selectivity and blood-brain barrier penetration, markedly improves prognosis. However, approximately 50% of patients develop resistance within 2 years, with mechanisms including ALK-dependent mutations, bypass pathway activation, and histological transformation. Mechanism-driven strategies include next-generation TKIs, combination therapies, immunotherapy, and repurposed agents. Dynamic monitoring via ctDNA liquid biopsy and genomic profiling guides precision treatment. This review summarizes alectinib's value, resistance mechanisms, and tailored strategies to optimize care for ALK-positive NSCLC.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Cell and Computational Epigenomics in HGSOC: A Roadmap to Overcoming Chemoresistance.","authors":"Samira A Farhadi, Issa S Al-Amri","doi":"10.2174/0115680096431715260319063002","DOIUrl":"https://doi.org/10.2174/0115680096431715260319063002","url":null,"abstract":"<p><strong>Background: </strong>High-Grade Serous Ovarian Cancer (HGSOC) remains the most lethal gynecologic malignancy, driven by profound molecular heterogeneity and dynamic epigenetic remodeling. Beyond well-characterized genomic alterations, emerging evidence underscores aberrant DNA methylation as a central regulator of lineage plasticity, tumor evolution, and chemoresistance.</p><p><strong>Objective: </strong>This review synthesizes recent advances demonstrating how computational deconvolution and single-cell DNA methylation technologies illuminate the epigenetic architecture of HGSOC, revealing cell-type-specific determinants of therapeutic resistance.</p><p><strong>Methods: </strong>We integrate findings from reference-based and reference-free deconvolution frameworks, single-cell bisulfite sequencing platforms, and multi-omic integrative tools such as SVA, EpiSCORE, and scDeconv, to provide a unified perspective on cell-resolved DNA methylation patterns in ovarian cancer.</p><p><strong>Results: </strong>These high-resolution epigenomic analyses reveal distinct methylation programs within chemoresistant subpopulations, notably cancer stem-like and EMT-associated cell states. Spatially informed methylation profiling further identifies microenvironmental niches that sustain resistance, offering new opportunities to define precise biomarkers and therapeutic vulnerabilities.</p><p><strong>Conclusion: </strong>The convergence of computational deconvolution and single-cell epigenomics provides a transformative framework for decoding chemoresistance in HGSOC. Embedding these technologies into clinical research promises to accelerate biomarker discovery, refine patient stratification, and guide the development of personalized therapeutic strategies aimed at overcoming treatment resistance.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ectophosphatase Activity in Human Hepatocellular Carcinoma Huh7 Cells: Characterisation and Implications for the Tumour Microenvironment.","authors":"Marco Antonio Lacerda-Abreu, Daniel Granato Da Costa Lima, Thais Russo-Abrahão, José Roberto Meyer-Fernandes","doi":"10.2174/0115680096439401260115052007","DOIUrl":"https://doi.org/10.2174/0115680096439401260115052007","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Hepatocellular carcinoma (HCC) is an aggressive liver malignancy characterised by extensive metabolic reprogramming and a complex tumour microenvironment (TME) in which inorganic phosphate (Pi) is crucial. Although ectophosphatases are known to regulate extracellular Pi through substrate dephosphorylation, their function in HCC has not been investigated. This study aimed to characterise ectophosphatase activity in HCC cells and to evaluate its potential contribution to tumour-associated processes.</p><p><strong>Methods: </strong>Ectophosphatase activity was assessed in the human HCC cell line Huh7. Enzymatic activity was determined by measuring p-nitrophenol (p-NP) release from p-nitrophenyl phosphate (p-NPP). Kinetic parameters, pH dependence, inhibitor sensitivity, and substrate specificity were analysed. Functional assays were performed to investigate the impact of enzyme inhibition on cell adhesion and migration.</p><p><strong>Results: </strong>Phosphatase activity was predominantly localised to the plasma membrane and followed Michaelis-Menten kinetics, with an apparent Km of 2.16 ± 0.49 mM and Vmax of 50.34 ± 4.45 nmol p-NP h⁻¹ per 10⁻⁵ cells. The activity increased under acidic conditions and was inhibited by sodium orthovanadate, sodium fluoride, and ammonium molybdate but remained unaffected by levamisole or tartrate. Hydrolysis of phosphotyrosine, phosphoserine, and phosphothreonine was detected, with orthovanadate selectively blocking p-NPP and phosphotyrosine hydrolysis, suggesting distinct catalytic sites. Inhibition of ectophosphatase activity significantly reduced Huh7 cell adhesion and migration.</p><p><strong>Discussion: </strong>These findings suggest that ectophosphatase activity contributes to key tumourrelated processes in HCC. By modulating phosphate metabolism in the extracellular environment, ectophosphatases may influence both the metabolic demands and the invasive properties of tumour cells.</p><p><strong>Conclusion: </strong>This study provides the first biochemical characterisation of ectophosphatase activity in HCC cells and highlights its potential role in shaping the TME, with implications for phosphate metabolism and tumour progression.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research Progress on Immunotherapy Targets in Nasopharyngeal Carcinoma.","authors":"Xiao Xiao, Qi Huang, Weiguo Huang","doi":"10.2174/0115680096411175251122045906","DOIUrl":"https://doi.org/10.2174/0115680096411175251122045906","url":null,"abstract":"<p><p>Nasopharyngeal carcinoma (NPC) ranks among the most prevalent malignant tu-mors and represents the most frequent type of ear, nose, and throat cancer. The Epstein-Barr virus (EBV) significantly contributes to the development of NPC. Characterized by high ma-lignancy and a tendency to metastasize, NPC generally exhibits moderate sensitivity to radia-tion therapy. Currently, the standard treatment for NPC involves a combination of radiotherapy and chemotherapy. In recent years, immunotherapy has emerged as a new strategy to treat malignant tumors, including NPC. The clinical objective of immunotherapy is to utilize the immune system to generate passive or active immunity against malignant tumors by targeting them. As a novel approach for treating malignant tumors, immunotherapy is gaining increasing popularity in clinical practice. It has demonstrated promising efficacy in the treatment of cer-tain malignant tumors and has become a current hotspot in clinical research. Based on pub-lished clinical data and ongoing trials, this article reviews the immunotherapy targets for NPC, with a focus on the clinical applications and progress of some targets. It mainly pays attention to the current research status of checkpoint inhibitors and vaccines for these targets, with the aim of providing inspiration for clinical practice and future clinical research.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147940148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HPGD Inhibited Natural Killer Cell Activation and Enhanced Autophagy to Promote the Progression of Papillary Thyroid Cancer by Activating the JAK2/STAT3 Pathway.","authors":"Jinfeng Lou, Yong Luo, Jiahui Yang, Ye Zhu, Cheng Li, Zheng Xu, Tebo Hua","doi":"10.2174/0115680096425628251130133650","DOIUrl":"https://doi.org/10.2174/0115680096425628251130133650","url":null,"abstract":"<p><strong>Background: </strong>HPGD is implicated in multiple cancers, but its role in papillary thy-roid cancer (PTC) remains unclear. This study aimed to investigate the role and potential mechanism of HPGD in PTC.</p><p><strong>Materials and methods: </strong>HPGD expression in PTC was analyzed using TCGA data. Kaplan-Meier survival and receiver operator characteristic (ROC) analyses were conducted to evaluate its prognostic and diagnostic value. Functional experiments were performed in TPC-1 cells with HPGD knockdown and overexpression to assess cell proliferation, migration, invasion, autophagy, and JAK/STAT signaling using colony formation, wound-healing, Transwell, and western blot analyses. The tumor immune microenvironment (TIME) was analyzed based on immune infiltration scores. The effect of HPGD on natural killer (NK) cell cytotoxicity was evaluated using a co-culture system with TPC-1 cells.</p><p><strong>Results: </strong>High HPGD expression was associated with poor prognosis. Functional experiments demonstrated that HPGD overexpression promoted PTC cell proliferation, migration, and in-vasion, while its knockdown had the opposite effect. Mechanistically, HPGD activated au-tophagy and the JAK2/STAT3 pathway. In the TIME, high HPGD expression was associated with increased immune and stromal scores but reduced NK cell infiltration. Moreover, HPGD overexpression suppressed NK cell cytotoxicity by reducing ICAM-1 expression, enhancing autophagy, and activating JAK2/STAT3.</p><p><strong>Discussion: </strong>This study reveals that HPGD exerts a tumor-promoting and immune-suppressive role in PTC, contrasting with its tumor-suppressive effects in other cancers. Its regulation of autophagy, JAK2/STAT3 signaling, and NK cell cytotoxicity highlights a cancer-type-specific mechanism.</p><p><strong>Conclusion: </strong>These findings suggest that targeting HPGD could be a potential therapeutic strat-egy for PTC.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147940050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of ncRNAs on Immunocyte Regulation and Antitumor Immune Responses in Cancer.","authors":"Yuhui Feng, Yicun Jiang, Jia Yu, Shengsong Tang, Guiqin Li, Xiaoyan Yang","doi":"10.2174/0115680096412559251128090503","DOIUrl":"https://doi.org/10.2174/0115680096412559251128090503","url":null,"abstract":"<p><p>Cancer persists as a formidable global health burden with profound impacts on hu-man morbidity. ncRNAs, constituting a major proportion of eukaryotic cellular transcripts, lack protein-coding capacity. Emerging evidence has elucidated the tissue-specific expression patterns and multifaceted regulatory roles of ncRNAs across malignancies. Through their ca-pacity to orchestrate gene networks and modulate the immune response within the tumor mi-croenvironment, ncRNAs emerge as pivotal regulators of oncogenesis and promising thera-peutic targets. Functionally distinct subclasses such as miRNAs, circRNAs, and lncRNAs ex-hibit unique mechanisms of action in tumor immunobiology. This study aims to provide a thorough examination of the attributes, roles, mechanisms, and their involvement in anti-tumor immune responses, as well as their interactions with immune cells in the cancer setting. While our understanding of ncRNAs is still in its early stages, this field holds significant promise for further investigation.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147940226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anlotinib for Advanced Peritoneal Follicular Dendritic Cell Sarcoma: A Case Report and Literature Revie.","authors":"Haiyun Geng, Fang Dai, Haiqing Hua, Mengran Cao, Xinlei Gong","doi":"10.2174/0115680096409948251215113303","DOIUrl":"https://doi.org/10.2174/0115680096409948251215113303","url":null,"abstract":"<p><strong>Introduction: </strong>Follicular dendritic cell sarcoma (FDCS) is a rare malignant tumor that lacks a standardized treatment plan. This report explores the efficacy and feasibility of the multi-target tyrosine kinase inhibitor (TKI) anlotinib as a first-line treatment through an indepth analysis of a case of advanced peritoneal FDCS.</p><p><strong>Case presentation: </strong>An 83-year-old female patient was enrolled and received oral anlotinib therapy due to advanced disease stage, poor physical condition, and her family's strong refusal of intravenous treatment. The treatment results showed that the patient achieved a significant partial response (PR), with a progression-free survival (PFS) of up to 15 months and an overall survival (OS) of 26 months, which far exceeded the treatment effects reported in the literature. Adverse reactions during anlotinib treatment were mild, and the lesions improved with increased dosages after the disease progressed, suggesting that this tumor may have adaptive rather than absolute resistance.</p><p><strong>Conclusion: </strong>This case provides valuable \"real-world\" evidence for the application of anlotinib in the treatment of advanced FDCS. Its success may stem from the close alignment between the drug's mechanism of action and the tumor's pathophysiology. However, this case also reveals unresolved issues, such as the complexity of FDCS diagnosis and the potential value of immunotherapy. Meanwhile, the clinical practice of targeted therapy further validates and promotes the value of molecular subtyping. Only by advancing the integration of molecular subtyping and targeted therapy can broader prospects be achieved for the precise diagnosis and treatment of FDCS.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Radiotherapy, Immune Checkpoint Inhibitors, and PIM Kinase Inhibition in Castration-Resistant Prostate Cancer.","authors":"Vignesh Chennupati, Matthew Eximond, Anita Nwiloh, Anne Rajkumar-Calkins, Jian Wang, Austin N Kirschner","doi":"10.2174/0115680096447552260409104759","DOIUrl":"10.2174/0115680096447552260409104759","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Immune checkpoint inhibitors (ICIs) have limited effi-cacy in prostate cancer. Radiation therapy (RT) combined with ICIs and PIM kinase inhibi-tion may enhance anti-tumor immune activity.</p><p><strong>Methods: </strong>RT-induced cytosolic double-stranded DNA (dsDNA) was measured in human and mouse prostate cancer cell lines as the surrogate upstream marker consistent with cGAS–STING engagement. In a syngeneic mouse model for castration-resistant prostate cancer (Myc-CaP in FVB mice), triple therapies were studied: (1) anti-CTLA-4, anti-PD-1, and RT, and (2) PIM kinase inhibitor PIM447, anti-PD-1, and RT. Mass cytometry (CyTOF) was used to measure the tumor-immune profile.</p><p><strong>Results: </strong>The peak induction of cytosolic dsDNA was at an RT dose of 13 Gy. In the mouse model, triple therapy with anti-CTLA-4, anti-PD-1, and RT doubled the median survival compared to monotherapy (32 days vs 11 to 22 days, p<0.006). Triple therapy with the PIM kinase inhibitor PIM447, anti-PD-1, and RT nearly tripled the median survival compared to PIM447 monotherapy (82 days vs 29 days, p=0.002). Mass cytometry analysis revealed that the combination of anti-PD-1 and RT reduced myeloid-derived suppressor cells and tissue-associated macrophages and enhanced CD8+ T-cell infiltration.</p><p><strong>Discussion: </strong>Although prostate cancer is an immunocold entity, RT can trigger immune ac-tivation, consistent with engagement of the cGAS–STING signaling pathway (cytosolic dsDNA serving as a surrogate upstream marker). In triple therapy, RT can enhance the effi-cacy of ICI and PIM-targeted drug therapy, significantly improving overall survival in a mouse model of CRPC.</p><p><strong>Conclusions: </strong>A combination of RT, ICIs, and PIM kinase inhibition may help overcome immune resistance in prostate cancer. This combination therapy approach supports further preclinical validation and careful clinical evaluation and warrants further clinical investiga-tion to optimize treatment strategies for CRPC.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13217420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PCK2 Promotes Non-Small Cell Lung Cancer Progression via SLC38A2- Mediated Glutamine Uptake and mTORC1 Activation.","authors":"Libo Ruan, Fan Zhang, Ling Xiao, Minjun Zhao, Kewang Xu, Wenjun Zeng, Haiyan Zhang","doi":"10.2174/0115680096423756251125052704","DOIUrl":"https://doi.org/10.2174/0115680096423756251125052704","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Phosphoenolpyruvate carboxykinase 2 (PCK2) contributes to cancer metabolic adaptation, yet its role in glutamine (Gln) transport and downstream signaling in non-small cell lung cancer (NSCLC) under glucose deprivation is unclear. This study aimed to investigate the PCK2-SLC38A2-mTORC1 axis in NSCLC under metabolic stress.</p><p><strong>Methods: </strong>A549 NSCLC cells were subjected to PCK2 knockdown using shRNA. Glutamine transporter expression was assessed via PRM proteomics and Western blot. Proliferation, migration, apoptosis, mTORC1 activity, and autophagy were analyzed under low-glucose conditions. Rescue assays were performed using Gln supplementation or SLC38A2 overexpression. Expression of PCK2 and SLC38A2 was evaluated in NSCLC tissues using immunohistochemistry.</p><p><strong>Results: </strong>PCK2 knockdown reduced Gln transporter levels, especially SLC38A2, and impaired cell proliferation and migration, while inducing apoptosis under low-glucose conditions. These effects were reversed by Gln supplementation or SLC38A2 overexpression. Mechanistically, PCK2 knockdown suppressed mTORC1 signaling and disrupted autophagy flux, both of which were restored by SLC38A2. Clinically, high expression of PCK2 and SLC38A2 was observed in NSCLC tissues and correlated with poor prognosis. Experimental results from both NSCLC patient-derived samples and tissue models demonstrated that downregulation of PCK2 effectively attenuated the progression of non-small cell lung cancer.</p><p><strong>Discussion: </strong>PCK2 promoted NSCLC cell survival and progression by maintaining Gln uptake through SLC38A2, thereby activating mTORC1 and modulating autophagy. These findings support a metabolic adaptation mechanism critical to tumor aggressiveness.</p><p><strong>Conclusion: </strong>The PCK2-SLC38A2-mTORC1 signaling axis sustains NSCLC cell viability under glucose limitation and represents a potential metabolic vulnerability for therapeutic targeting.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}