Cancer lettersPub Date : 2025-04-10DOI: 10.1016/j.canlet.2025.217715
Yidi Tai , Lulu Kong , Yan Wang , Dongyu Zhao , Xu Chen , Qingnan Wu , Jia Hao , Xi Wang , Xingyang Liu , Dongshao Chen , Jinting Li , Yuying Hu , Weimin Zhang , Cai-Hong Yun , Qimin Zhan
{"title":"Identification and characterization of Bufalin as a novel EGFR degrader","authors":"Yidi Tai , Lulu Kong , Yan Wang , Dongyu Zhao , Xu Chen , Qingnan Wu , Jia Hao , Xi Wang , Xingyang Liu , Dongshao Chen , Jinting Li , Yuying Hu , Weimin Zhang , Cai-Hong Yun , Qimin Zhan","doi":"10.1016/j.canlet.2025.217715","DOIUrl":"10.1016/j.canlet.2025.217715","url":null,"abstract":"<div><div>Esophageal squamous cell carcinoma (ESCC) stands out as a common cancer type worldwide, characterized by its notably high rates of occurrence and mortality. The epidermal growth factor receptor (EGFR) is one of the main targets for cancer treatment as it is one of the genes whose expression is often altered by overexpression, amplification, and mutation in a variety of solid tumors. Substantial efforts have been made to develop EGFR-targeted therapeutic agents, including monoclonal antibodies and tyrosine kinase inhibitors (TKIs). However, these agents exhibited limited efficacy due to the emergence of acquired resistance. Therefore, novel treatment strategies targeting EGFR are urgently needed. Recent studies have identified a few natural compounds that can efficiently inhibit EGFR, indicating that natural products may be potential sources for the development of new EGFR inhibitors. Here, using the Drug Affinity Responsive Target Stability (DARTS) assay combined with liquid chromatography/tandem mass spectrometry analysis, co-crystal method, we discovered that Bufalin directly interacts with EGFR and causes EGFR endocytosis and degradation in the lysosome. Moreover, Bufalin exhibits superior anti-tumor activity compared with another EGFR TKIs. Our study identified Bufalin as the first natural small-molecule EGFR degrader, which suppresses EGFR signaling by inducing the degradation of EGFR via the endosome-lysosome pathway.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"623 ","pages":"Article 217715"},"PeriodicalIF":9.1,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143883104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer lettersPub Date : 2025-04-09DOI: 10.1016/j.canlet.2025.217694
Shanghua Cai , Yulin Deng , Zhihao Zou , Weicheng Tian , Zhenfeng Tang , Jinchuang Li , Zeheng Tan , Zhenjie Wu , Zhaodong Han , Biyan Wen , Yuanfa Feng , Ren Liu , Xuejin Zhu , Yongding Wu , Haiyin Xiao , Huichan He , Jianheng Ye , Weide Zhong
{"title":"Metformin inhibits the progression of castration-resistant prostate cancer by regulating PDE6D induced purine metabolic alternation and cGMP / PKG pathway activation","authors":"Shanghua Cai , Yulin Deng , Zhihao Zou , Weicheng Tian , Zhenfeng Tang , Jinchuang Li , Zeheng Tan , Zhenjie Wu , Zhaodong Han , Biyan Wen , Yuanfa Feng , Ren Liu , Xuejin Zhu , Yongding Wu , Haiyin Xiao , Huichan He , Jianheng Ye , Weide Zhong","doi":"10.1016/j.canlet.2025.217694","DOIUrl":"10.1016/j.canlet.2025.217694","url":null,"abstract":"<div><div>The castration-resistant prostate cancer (CRPC) remains an incurable disease. Metformin has demonstrated a potential therapeutic effect on CRPC. However, the poor clinical performance of metformin against cancer may be due to its clinical dose being much lower than the anticancer concentration used in pre-clinical experiments. The challenge is to determine a way to enhance sensitivity to metformin at an appropriate concentration on CRPC. In this study, a mouse model of low-dose metformin treatment for CRPC cells were established. Metabolomic-seq and transcriptomic-seq was used to investigate changes in CRPC xenografts. We discovered that low-dose metformin inhibits the progression of CRPC by regulating PDE6D, which induces alterations in purine metabolism and activates the cGMP/PKG pathway. Furthermore, we found that cells with high expression of PDE6D were more resistant to metformin. When combined with the PDE6D inhibitor TMX-4100, the inhibitory effect on tumors was enhanced, and TMX-4100 demonstrated favorable biosafety in animal models. In conclusion, we found that low-dose metformin inhibits the progression of CRPC by regulating PDE6D-induced alterations in purine metabolism and activating the cGMP/PKG pathway. Moreover, patients with high PDE6D expression may exhibit greater resistance to metformin. Combining metformin with TMX-4100 could further improve the inhibitory effects on tumors.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"622 ","pages":"Article 217694"},"PeriodicalIF":9.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer lettersPub Date : 2025-04-09DOI: 10.1016/j.canlet.2025.217710
Jinhan Zhou , Yi Xu , Yining Li , Qiyue Zhang , Liang Zhong , Weiyi Pan , Keyan Ji , Shangjun Zhang , Zhuo Chen , Yu Liu , Lijie Fan , Chuanxia Liu , Qianming Chen , Zhiyong Wang
{"title":"Cancer-associated fibroblasts derived amphiregulin promotes HNSCC progression and drug resistance of EGFR inhibitor","authors":"Jinhan Zhou , Yi Xu , Yining Li , Qiyue Zhang , Liang Zhong , Weiyi Pan , Keyan Ji , Shangjun Zhang , Zhuo Chen , Yu Liu , Lijie Fan , Chuanxia Liu , Qianming Chen , Zhiyong Wang","doi":"10.1016/j.canlet.2025.217710","DOIUrl":"10.1016/j.canlet.2025.217710","url":null,"abstract":"<div><div>In clinical oncology, lack of sustained treatment response is very common in cancer patients and largely limits the efficiency of most anticancer targeted-therapies. While anti-EGFR therapeutics have been extensively employed in head and neck squamous cell carcinoma (HNSCC) management, their clinical efficacy remains limited due to unresolved resistance mechanisms. Notably, the functional role of EGFR ligand proteins in both tumor progression and therapeutic response has not been fully elucidated. Here we reveal that amphiregulin (AREG) as a potential driver of drug resistance of EGFR-targeted treatment in HNSCC patients. We identify a PDGFRβ<sup>+</sup>FAP<sup>+</sup>αSMA<sup>+</sup> myofibroblast (myCAF) subset as the major source of AREG in tumor microenvironment. TCGA database and clinical cohort demonstrated that patients with high AREG expression exhibited significantly higher lymph node metastasis rates (59.35 %) and poorer prognosis (median 5-year survival: 2.2 years). In contrast, patients with low AREG expression showed reduced metastatic potential (metastasis rate: 45.16 %) and more favorable clinical outcomes (median 5-year survival: 4.8 years). Mechanistically, AREG promotes vascular mimicry formation via epithelial-endothelial transition of tumor cells to offer extra blood supply and metastasis channels. Further, live-cell imaging revealed that AREG induces plasma membrane stabilization of over 90 % receptor proteins while concurrently enhancing receptor recycling, driving EGFR inhibitor resistance. Collectively, our study reveals the crucial role of AREG in tumor landscape, informing a new predictive biomarker of EGFR inhibitor efficiency as well as a new potential therapeutic target of HNSCC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"622 ","pages":"Article 217710"},"PeriodicalIF":9.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer lettersPub Date : 2025-04-09DOI: 10.1016/j.canlet.2025.217713
Jiatong Tang , Xiaoyang Li , Neng Tang , Xiawen Lin , Yixiang Du , Shuo Zhang , Qi Li , Yifan Zhang , Yixuan Zhang , Hexing Hang , Tongtong Qiu , Yudong Qiu , Hao Cheng , Zhan Dai , Hao Hong , Wei Wei , Jian He , Chao Yan
{"title":"CD44 identified as a diagnostic biomarker for highly malignant CA19-9 negative pancreatic cancer","authors":"Jiatong Tang , Xiaoyang Li , Neng Tang , Xiawen Lin , Yixiang Du , Shuo Zhang , Qi Li , Yifan Zhang , Yixuan Zhang , Hexing Hang , Tongtong Qiu , Yudong Qiu , Hao Cheng , Zhan Dai , Hao Hong , Wei Wei , Jian He , Chao Yan","doi":"10.1016/j.canlet.2025.217713","DOIUrl":"10.1016/j.canlet.2025.217713","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited diagnostic biomarkers. Carbohydrate antigen 19-9 (CA19-9) is a widely used clinical biomarker and is generally considered to correlate with PDAC malignancy. However, the relationship between CA19-9 expression levels and tumor aggressiveness remains underexplored. In this study, we report a biphasic relationship between CA19-9 expression levels and PDAC malignancy, where both negative (<5 U/mL) and high (>37 U/mL) CA19-9 levels are associated with increased tumor aggressiveness. We defined CA19-9 negative PDAC as tumors that lack CA19-9 expression intracellulary, on the cell membrane, and in secreted form. In PDAC cell lines and patient-derived organoids, CA19-9 negativity, confirmed by immunofluorescence, flow cytometry and ELISA, correlated with more aggressive behaviors. In PDAC patients, tumors from those with serum CA19-9 levels below 5 U/mL exhibited stronger metabolically activity, more immunosuppressive tumor microenvironment, and worse survival than CA19-9 positive tumors, with over 90 % showing absent CA19-9 expression by immunohistochemistry (IHC). Glycoproteomics profiling identified CD44 as a highly expressed biomarker in CA19-9 negative PDAC. Elevated CD44 expression effectively distinguished CA19-9 negative PDAC from both CA19-9 positive PDAC and CA19-9 negative benign pancreatic diseases, suggesting its potential as a diagnostic tool. Furthermore, we developed a radionuclide-labeled CD44 antibody <sup>89</sup>Zr-1M2E3, which specifically recognized CA19-9 negative PDAC tumors in preclinical models using PET-CT imaging. These findings highlight CD44 as a promising biomarker and therapeutic target for diagnosing and treating CA19-9 negative PDAC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"622 ","pages":"Article 217713"},"PeriodicalIF":9.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer lettersPub Date : 2025-04-08DOI: 10.1016/j.canlet.2025.217714
Qi Wang , Tanqing Long , Peijuan Tang , Chuanrui Xu , Liang Wang , Juan Liu
{"title":"Metabolic reprogramming in cholangiocarcinoma cancer stem cells: Emerging therapeutic paradigms","authors":"Qi Wang , Tanqing Long , Peijuan Tang , Chuanrui Xu , Liang Wang , Juan Liu","doi":"10.1016/j.canlet.2025.217714","DOIUrl":"10.1016/j.canlet.2025.217714","url":null,"abstract":"<div><div>Cholangiocarcinoma (CCA) is an aggressive malignancy characterized by limited therapeutic options and poor prognosis, largely attributed to the presence of cancer stem cells (CSCs). These CSCs serve as pivotal drivers of tumor heterogeneity, chemotherapy resistance, and disease recurrence. CSCs in CCA exhibit remarkable plasticity, a characteristic sustained through metabolic state alterations and intricate interactions with the tumor microenvironment (TME), which collectively enhance their self-renewal and survival potential. While advancements have been made in understanding metabolic reprogramming of CCA CSCs, translating these findings into clinical applications encounters significant challenges, including insufficient target specificity, complex metabolic heterogeneity, and the profound complexity of the TME. This review provides a systematic evaluation of metabolic reprogramming mechanisms in CCA CSCs, with critical analysis of stemness-maintaining signaling pathways, oxidative phosphorylation (OXPHOS), nutrient utilization, metabolic crosstalk within the TME, autophagy regulation, and ferroptosis resistance. We emphasize emerging strategies to therapeutically target the interconnected metabolic networks essential for CSC functionality and survival, with the goal of establishing a theoretical basis for innovative precision therapies to enhance clinical outcomes for CCA patients.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"622 ","pages":"Article 217714"},"PeriodicalIF":9.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer lettersPub Date : 2025-04-08DOI: 10.1016/j.canlet.2025.217681
Mina Nikanjam , Judith Pérez-Granado , Mark Gramling , Bruno Larvol , Razelle Kurzrock
{"title":"Nectin-4 expression patterns and therapeutics in oncology","authors":"Mina Nikanjam , Judith Pérez-Granado , Mark Gramling , Bruno Larvol , Razelle Kurzrock","doi":"10.1016/j.canlet.2025.217681","DOIUrl":"10.1016/j.canlet.2025.217681","url":null,"abstract":"<div><div>Nectin-4 is a transmembrane receptor that is implicated in migration, adhesion, and proliferation of tumor cells. It has minimal expression in healthy adult tissue but is overexpressed in a number of cancers, with higher expression levels seen in breast, bladder, colorectal, gallbladder, gastric, and non-small cell lung cancers. Enfortumab vedotin is an antibody-drug conjugate against nectin-4 that has been studied in a number of solid tumors and is FDA-approved for advanced urothelial cancers (including in combination with pembrolizumab). There are a number of other nectin-4-targeting agents under investigation. This review summarizes nectin-4 expression (membranous and cytoplasmic)/amplification in cancer and its potential as a response biomarker, as well as clinical trials of enfortumab vedotin and novel nectin-4 targeting agents. Biomarker-driven approaches merit investigation for nectin-4 directed across tumor types.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"622 ","pages":"Article 217681"},"PeriodicalIF":9.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Phase 3 randomized study of physician choice vs metronomic chemotherapy in platinum refractory/ineligible head and neck cancer in palliative setting with survival outcomes","authors":"Rushabh Kothari , Vijay Patil , Ravi krishna Madala , Ravikant Singh , Vikas T. Talreja , Anand Pathak , Sameer Shrirangwar , Tanmoy Kumar Mandal , Sudeep Das , Siddharth Turkar , Nikhil Pande , Arun Chandrasekharan , Gunjesh Singh , Tara Chand Gupta , Bhavesh Poladia , Manuprasad Avaronnan , Lovin Wilson , Nirmal Raut , Monica Jadhav , Mitali Alone , Kumar Prabhash","doi":"10.1016/j.canlet.2025.217702","DOIUrl":"10.1016/j.canlet.2025.217702","url":null,"abstract":"<div><div>There are multiple options of treatment in second line therapy for locally advanced head and neck squamous cell carcinoma (LAHNSCC) treated with palliative intent. However, triple metronomic chemotherapy is oral, cost-effective, and resource-efficient. Hence this phase 3 randomized trial compares National Comprehensive Cancer Network (NCCN) recommended physician choice therapy versus triple metronomic chemotherapy (TMC) in the second-line treatment of head and neck cancer This study, designed to establish superiority, was conducted in India across 16 sites under the Cancer Research Statistics Foundation. The study recruited 114 LAHNSCC who were treated with palliative intent in second line. These patients underwent 1:1 central stratified randomization to either triple metronomic chemotherapy or physician choice therapy (taxane, 5fu/capecitabine, afatinib, nivolumab/pembrolizumab, cetuximab).At a median follow-up of 258 (95 % CI 209–306) days, the median overall survival of the triple metronomic chemotherapy was 181 days (95 %CI 142.7–219.2) versus 123 days (95 %CI 94–152) in the physician choice therapy arm (P = 0.00.002). The median progression free survival was 120 days (95 %CI 89.2–150.8) versus 70 days (95 % CI 58.2–81.8) in metronomic chemotherapy and in the physician choice therapy arms respectively (P < 0.001).These results suggest that TMC significantly improves survival outcomes over physician choice therapy in platinum-refractory head and neck cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"621 ","pages":"Article 217702"},"PeriodicalIF":9.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143854920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer lettersPub Date : 2025-04-07DOI: 10.1016/j.canlet.2025.217699
Konstantin Bräutigam , Kristijan Skok , Krzysztof Szymonski , Charlotte Vestrup Rift , Eva Karamitopoulou
{"title":"Tumor immune microenvironment in pancreatic ductal adenocarcinoma revisited – Exploring the “Space”","authors":"Konstantin Bräutigam , Kristijan Skok , Krzysztof Szymonski , Charlotte Vestrup Rift , Eva Karamitopoulou","doi":"10.1016/j.canlet.2025.217699","DOIUrl":"10.1016/j.canlet.2025.217699","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly malignancies with a highly immunosuppressive tumor immune microenvironment (TIME) that hinders effective therapy. PDAC is characterized by significant heterogeneity in immune cell composition, spatial distribution and activation states, which impacts tumor progression and treatment response. Tumour-infiltrating lymphocytes (TILs), including CD4<sup>+</sup> T-helper cells, CD8<sup>+</sup> cytotoxic T-cells and FOXP3<sup>+</sup> regulatory T-cells, play a key role in immune regulation, yet PDAC is largely an immunologically “cold” tumour with limited effector T-cell infiltration. The surrounding cellular microenvironment, particularly Cancer Associated Fibroblasts (CAFs) and macrophages, contributes to immune evasion by promoting a fibrotic and desmoplastic barrier that limits TIL infiltration. The prognostic significance of TILs is increasingly recognized, with higher densities correlating with improved survival, whereas regulatory T-cell infiltration and immunosuppressive stromal interactions are associated with poor outcomes. Emerging therapeutic strategies targeting the TIME (e.g., CAFs), immune checkpoint inhibitors, and TIL-based therapies offer the potential to overcome resistance. Future research must focus on optimizing immunotherapy strategies and unravelling the complex stromal-immune interactions to improve clinical translation.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"622 ","pages":"Article 217699"},"PeriodicalIF":9.1,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer lettersPub Date : 2025-04-07DOI: 10.1016/j.canlet.2025.217691
Ines Pulido , Qiyue Luan , Sara Pastor-Puente , Laura Gunder , Yaya Wang , Chenghao Ying , Jinhua Li , Yuetong Sun , Yan Dai , Christian Ascoli , Khaled Abdelhady , Malek Massad , Thomas L. Prince , Guoqiang Wang , Kevin P. Foley , Weiwen Ying , Ian Papautsky , Julian Carretero , Takeshi Shimamura
{"title":"Chaperone directed heterobifunctional molecules circumvent KRASG12C inhibitor resistance","authors":"Ines Pulido , Qiyue Luan , Sara Pastor-Puente , Laura Gunder , Yaya Wang , Chenghao Ying , Jinhua Li , Yuetong Sun , Yan Dai , Christian Ascoli , Khaled Abdelhady , Malek Massad , Thomas L. Prince , Guoqiang Wang , Kevin P. Foley , Weiwen Ying , Ian Papautsky , Julian Carretero , Takeshi Shimamura","doi":"10.1016/j.canlet.2025.217691","DOIUrl":"10.1016/j.canlet.2025.217691","url":null,"abstract":"<div><div>While KRAS<sup>G12C</sup> inhibitors have shown promising results in clinical activity, acquired resistance remains a significant barrier to durable responses. Combination therapies have been explored to improve the efficacy of KRAS<sup>G12C</sup> inhibitors; however, their use is often restricted due to toxicity and limitations in clinically amenable dosing schedules. Transcriptomic profiling and functional assays on acquired resistant models to adagrasib identified an enrichment of HSP90 client proteins in resistant phenotypes, suggesting a therapeutic vulnerability. To address the finding, RNK07421, a novel heterobifunctional molecule, was developed to simultaneously target KRAS<sup>G12C</sup> and HSP90-client oncoproteins. Structural and biochemical analyses demonstrated that RNK07421 disrupts KRAS<sup>G12C</sup> interactions by inducing a non-natural interface with HSP90, thereby impairing oncogenic signaling. In vitro, RNK07421 effectively suppressed ERK reactivation and reduced viability in KRAS<sup>G12C</sup>-mutant cell lines exhibiting either intrinsic or acquired resistance. <em>In vivo</em>, RNK07421 significantly reduced tumor burden in xenograft models, outperforming both monotherapies and combination therapies. These findings highlight dual KRAS<sup>G12C</sup> and HSP90 inhibition as a promising strategy to overcome resistance in KRAS<sup>G12C</sup>-driven cancers.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"622 ","pages":"Article 217691"},"PeriodicalIF":9.1,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143883197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer lettersPub Date : 2025-04-05DOI: 10.1016/j.canlet.2025.217697
Xiangfei Xue , Manyuan Wang , Jiangtao Cui , Minying Yang , Lifang Ma , Rui Kang , Daolin Tang , Jiayi Wang
{"title":"Glutathione metabolism in ferroptosis and cancer therapy","authors":"Xiangfei Xue , Manyuan Wang , Jiangtao Cui , Minying Yang , Lifang Ma , Rui Kang , Daolin Tang , Jiayi Wang","doi":"10.1016/j.canlet.2025.217697","DOIUrl":"10.1016/j.canlet.2025.217697","url":null,"abstract":"<div><div>Glutathione (GSH), a non-enzymatic antioxidant in mammalian cells, plays an essential role in maintaining redox balance, mitigating oxidative stress, and preserving cellular homeostasis. Beyond its well-established function in detoxifying reactive oxygen species (ROS), GSH serves as a critical regulator of ferroptosis—an iron-dependent form of cell death marked by excessive lipid peroxidation. Serving as a cofactor for glutathione peroxidase 4 (GPX4), GSH catalyzes the conversion of lipid peroxides into non-toxic lipid alcohols, thereby preventing the accumulation of deleterious lipid oxidation products and halting the spread of oxidative damage. In cancer cells, upregulated GSH synthesis and GPX4 activity contribute to an enhanced antioxidant defense, countering oxidative stress provoked by increased metabolic demands and exposure to therapeutic agents such as chemotherapy, radiotherapy, and immunotherapy. This ability of cancer cells to modulate their ferroptosis susceptibility through GSH metabolism underscores its potential as a therapeutic target. Additionally, GSH influences several key oncogenic and tumor-suppressive signaling pathways, including NFE2L2/NRF2, TP53/p53, NF-κB, Hippo, and mTOR, which collectively regulate responses to oxidative stress, affect metabolic processes, and modulate sensitivity to ferroptosis in cancer cells. This review explores recent advancements in understanding GSH's multifaceted role in ferroptosis, emphasizing its implications for cancer biology and therapeutic interventions.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"621 ","pages":"Article 217697"},"PeriodicalIF":9.1,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
