Pub Date : 2025-11-25DOI: 10.1038/s41388-025-03637-0
Marina Chan, Taranjit S. Gujral
Precision oncology is increasingly moving beyond genomics alone to approaches that directly test how patient tumors respond to therapy. This shift reflects a central challenge in oncology, where sequencing alone often fails to identify effective therapies for rare, treatment-resistant, or genomically ambiguous tumors. Here, we highlight three-dimensional (3D) microtumor models as a powerful functional platform that preserves the architecture, cell types, and microenvironment of intact tumors for drug screening. By capturing biology that 2D models and genomics alone miss, this approach enables more accurate prediction of therapeutic vulnerabilities and expands the precision-oncology toolkit for patients who currently lack actionable options.
{"title":"Beyond genomics: 3D microtumor assays for rapid, clinically relevant functional drug testing","authors":"Marina Chan, Taranjit S. Gujral","doi":"10.1038/s41388-025-03637-0","DOIUrl":"10.1038/s41388-025-03637-0","url":null,"abstract":"Precision oncology is increasingly moving beyond genomics alone to approaches that directly test how patient tumors respond to therapy. This shift reflects a central challenge in oncology, where sequencing alone often fails to identify effective therapies for rare, treatment-resistant, or genomically ambiguous tumors. Here, we highlight three-dimensional (3D) microtumor models as a powerful functional platform that preserves the architecture, cell types, and microenvironment of intact tumors for drug screening. By capturing biology that 2D models and genomics alone miss, this approach enables more accurate prediction of therapeutic vulnerabilities and expands the precision-oncology toolkit for patients who currently lack actionable options.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 50","pages":"4910-4915"},"PeriodicalIF":7.3,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595390","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}
Pub Date : 2025-11-25DOI: 10.1038/s41388-025-03634-3
David J. Wisniewski, Donna Voeller, Yonit A. Addissie, Sachin Kumar Deshmukh, Sharon Wu, Maryam B. Lustberg, Darawalee Wangsa, Danny Wangsa, Kerstin Heselmeyer-Haddad, Yoshimi Endo Greer, George W. Sledge, Stanley Lipkowitz
EGFR family receptor tyrosine kinase signaling is commonly dysregulated in cancer by amplification or activating mutations. Although studies have investigated dual EGFR/PI3K inhibition in breast cancer, they have not determined biomarkers which predict success. We present evidence of a patient subset with EGFR amplification and PI3Kinase pathway mutations in breast cancer which can be synergistically targeted by dual EGFR/PI3K inhibition. This study identified that EGFR amplification occurs in ~1–5% of breast cancer patients with shorter overall survival compared to unamplified patients. Up to 71% of EGFR amplified tumors have activating mutations in the PI3K pathway. Dual EGFR/PI3K inhibition more dramatically reduced mTOR and AKT signaling in BT20 and MDA-MB-468 cells which both have EGFR amplification and PI3K pathway activating mutations, compared to control cells. Dual inhibition synergistically reduced cell viability and increased apoptosis in MDA-MB-468 and BT20 compared to control. Single agent therapy in a BT20 xenograft model reduced tumor volume, however only the combination statistically significantly reduced tumor volume compared to control. We conclude that EGFR amplification with co-incident PI3K pathway mutations are driver mutations in a subset of breast cancers and present a subgroup of breast cancers that are more likely to respond to dual targeted therapy.
{"title":"EGFR amplification and PI3K pathway mutations identify a subset of breast cancers that synergistically respond to EGFR and PI3K inhibition","authors":"David J. Wisniewski, Donna Voeller, Yonit A. Addissie, Sachin Kumar Deshmukh, Sharon Wu, Maryam B. Lustberg, Darawalee Wangsa, Danny Wangsa, Kerstin Heselmeyer-Haddad, Yoshimi Endo Greer, George W. Sledge, Stanley Lipkowitz","doi":"10.1038/s41388-025-03634-3","DOIUrl":"10.1038/s41388-025-03634-3","url":null,"abstract":"EGFR family receptor tyrosine kinase signaling is commonly dysregulated in cancer by amplification or activating mutations. Although studies have investigated dual EGFR/PI3K inhibition in breast cancer, they have not determined biomarkers which predict success. We present evidence of a patient subset with EGFR amplification and PI3Kinase pathway mutations in breast cancer which can be synergistically targeted by dual EGFR/PI3K inhibition. This study identified that EGFR amplification occurs in ~1–5% of breast cancer patients with shorter overall survival compared to unamplified patients. Up to 71% of EGFR amplified tumors have activating mutations in the PI3K pathway. Dual EGFR/PI3K inhibition more dramatically reduced mTOR and AKT signaling in BT20 and MDA-MB-468 cells which both have EGFR amplification and PI3K pathway activating mutations, compared to control cells. Dual inhibition synergistically reduced cell viability and increased apoptosis in MDA-MB-468 and BT20 compared to control. Single agent therapy in a BT20 xenograft model reduced tumor volume, however only the combination statistically significantly reduced tumor volume compared to control. We conclude that EGFR amplification with co-incident PI3K pathway mutations are driver mutations in a subset of breast cancers and present a subgroup of breast cancers that are more likely to respond to dual targeted therapy.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 1","pages":"15-25"},"PeriodicalIF":7.3,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03634-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145605294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neddylation, a post-translational modification process involving three enzymatic steps, is crucial in regulating various cancers. However, its specific mechanisms in pancreatic cancer (PC) remain largely unexplored. This study focused on screening neddylation-related molecules in PC and identified RNF187 as a key player, demonstrating its overexpression in PC and its ability to enhance cell proliferation and invasion both in vitro and in vivo. Notably, NEDD8 could bind to RNF187, preventing its degradation via K48-linked ubiquitination. This interaction stabilized RNF187, leading to increased protein levels and subsequent stimulation of PC cell proliferation and invasion. However, this mechanism alone did not fully account for how RNF187 could exacerbate PC malignancy. Further research revealed that RNF187 upregulated IQGAP1 protein levels through modulation of K48- and K63-linked ubiquitination. This post-translational modification triggered the rearrangement of the actin cytoskeleton in PC cells by altering the transcriptional levels of MYH9, thereby promoting PC malignancy. Overall, our findings demonstrate that neddylation of RNF187 enhances PC malignancy through the IQGAP1/MYH9 axis, suggesting a new therapeutic target for PC.
{"title":"RNF187 neddylation in pancreatic cancer activates malignancy via IQGAP1-dependent actin cytoskeleton rearrangement","authors":"Chengxiao Yang, Xinyuan Liu, Wenbo Yang, Lingwen Wang, Ziheng Wang, Jiaming Li, Feng Li, Chundong Cheng, Xuewei Bai, Bei Sun, Hongze Chen","doi":"10.1038/s41388-025-03639-y","DOIUrl":"10.1038/s41388-025-03639-y","url":null,"abstract":"Neddylation, a post-translational modification process involving three enzymatic steps, is crucial in regulating various cancers. However, its specific mechanisms in pancreatic cancer (PC) remain largely unexplored. This study focused on screening neddylation-related molecules in PC and identified RNF187 as a key player, demonstrating its overexpression in PC and its ability to enhance cell proliferation and invasion both in vitro and in vivo. Notably, NEDD8 could bind to RNF187, preventing its degradation via K48-linked ubiquitination. This interaction stabilized RNF187, leading to increased protein levels and subsequent stimulation of PC cell proliferation and invasion. However, this mechanism alone did not fully account for how RNF187 could exacerbate PC malignancy. Further research revealed that RNF187 upregulated IQGAP1 protein levels through modulation of K48- and K63-linked ubiquitination. This post-translational modification triggered the rearrangement of the actin cytoskeleton in PC cells by altering the transcriptional levels of MYH9, thereby promoting PC malignancy. Overall, our findings demonstrate that neddylation of RNF187 enhances PC malignancy through the IQGAP1/MYH9 axis, suggesting a new therapeutic target for PC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 1","pages":"26-41"},"PeriodicalIF":7.3,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03639-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145605263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transcriptional dysregulation has emerged as a critical driver of melanoma progression, yet the molecular mechanisms governing this process and their potential as therapeutic targets remain inadequately characterized. Here, we identify FRA1 as a potent and actionable driver of melanoma metastasis. FRA1 enhanced both the initial seeding and subsequent outgrowth of metastatic lesions. Comprehensive multi-omics integration revealed transcriptional target genes of FRA1, with AXL, CDK6, and FSCN1 exhibiting increased expression in melanoma metastasis and a significant correlation with poor patient outcomes. Silencing AXL, CDK6, or FSCN1 abrogated FRA1-mediated invasion in vitro and reduced metastatic colonization. Furthermore, pharmacological inhibition of CDK6 and FSCN1, and to a lesser extent AXL, suppressed melanoma metastasis and prolonged overall survival. The expression of FRA1 and its target genes correlates with shortened survival across multiple cancer types, highlighting the broader clinical relevance of this pathway. This study unveils an actionable FRA1-mediated transcriptional network that drives cancer progression and metastasis, offering potential avenues for therapeutic interventions.
{"title":"FRA1 drives melanoma metastasis through an actionable transcriptional network","authors":"Xiaonan Xu, Vinesh Jarajapu, Manon Chadourne, Zulaida Soto-Vargas, Shaaron L. Ochoa-Rios, Neel Jasani, Kaizhen Wang, Nicol Mecozzi, Jiqiang Yao, Xiaoqing Yu, Florian A. Karreth","doi":"10.1038/s41388-025-03632-5","DOIUrl":"10.1038/s41388-025-03632-5","url":null,"abstract":"Transcriptional dysregulation has emerged as a critical driver of melanoma progression, yet the molecular mechanisms governing this process and their potential as therapeutic targets remain inadequately characterized. Here, we identify FRA1 as a potent and actionable driver of melanoma metastasis. FRA1 enhanced both the initial seeding and subsequent outgrowth of metastatic lesions. Comprehensive multi-omics integration revealed transcriptional target genes of FRA1, with AXL, CDK6, and FSCN1 exhibiting increased expression in melanoma metastasis and a significant correlation with poor patient outcomes. Silencing AXL, CDK6, or FSCN1 abrogated FRA1-mediated invasion in vitro and reduced metastatic colonization. Furthermore, pharmacological inhibition of CDK6 and FSCN1, and to a lesser extent AXL, suppressed melanoma metastasis and prolonged overall survival. The expression of FRA1 and its target genes correlates with shortened survival across multiple cancer types, highlighting the broader clinical relevance of this pathway. This study unveils an actionable FRA1-mediated transcriptional network that drives cancer progression and metastasis, offering potential avenues for therapeutic interventions.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 50","pages":"4895-4909"},"PeriodicalIF":7.3,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03632-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1038/s41388-025-03647-y
Zhiqiang Wu, Meixi Wang, Xiaohan Dong, Yanchen Sun, Lu Zhang, Mi Tang, Xiangli Jiang, Yu Guo, Jing Wang, Weiwei Wang, Zhiyong Yuan, Zeyun Mi
Lung cancer, especially the subgroup non-small cell lung cancer (NSCLC), continues to be one of the most commonly diagnosed cancers and the leading cause of cancer-related deaths worldwide. Cisplatin has long been a cornerstone of chemotherapy and has improved the prognosis for NSCLC patients. However, its overall efficacy remains unsatisfactory, and patients ultimately develop drug resistance. Uncovering the underlying mechanism and identifying potential target to enhance cisplatin chemosensitivity is urgent. In this study, we uncovered that OTU deubiquitinase 1 (OTUD1) plays an important role in orchestrating cisplatin chemosensitivity of NSCLC. We found that promoter methylation resulted in downregulation of OTUD1 and the downregulated OTUD1 significantly associates with cisplatin resistance and poor prognosis in NSCLC. Overexpression of OTUD1 enhances cisplatin sensitivity in vitro and in vivo. Mechanistically, OTUD1 promoted the degradation of RAD23B-XPC complex, which is the critical factor for nucleotide excision repair to remove cisplatin-induced DNA adducts, leading to cisplatin-induced cell death. OTUD1 cleaves the K63-linked ubiquitin chain of RAD23B and XPC, and enhances PRKN mediated K48-linked ubiquitination of RAD23B-XPC and the subsequent proteasomal degradation. The findings of this study highlighted that OTUD1 could be a potential therapeutic target for NSCLC.
{"title":"The deubiquitinase OTUD1 orchestrates cisplatin chemosensitivity of non-small cell lung cancer through destabilizing RAD23B/XPC","authors":"Zhiqiang Wu, Meixi Wang, Xiaohan Dong, Yanchen Sun, Lu Zhang, Mi Tang, Xiangli Jiang, Yu Guo, Jing Wang, Weiwei Wang, Zhiyong Yuan, Zeyun Mi","doi":"10.1038/s41388-025-03647-y","DOIUrl":"10.1038/s41388-025-03647-y","url":null,"abstract":"Lung cancer, especially the subgroup non-small cell lung cancer (NSCLC), continues to be one of the most commonly diagnosed cancers and the leading cause of cancer-related deaths worldwide. Cisplatin has long been a cornerstone of chemotherapy and has improved the prognosis for NSCLC patients. However, its overall efficacy remains unsatisfactory, and patients ultimately develop drug resistance. Uncovering the underlying mechanism and identifying potential target to enhance cisplatin chemosensitivity is urgent. In this study, we uncovered that OTU deubiquitinase 1 (OTUD1) plays an important role in orchestrating cisplatin chemosensitivity of NSCLC. We found that promoter methylation resulted in downregulation of OTUD1 and the downregulated OTUD1 significantly associates with cisplatin resistance and poor prognosis in NSCLC. Overexpression of OTUD1 enhances cisplatin sensitivity in vitro and in vivo. Mechanistically, OTUD1 promoted the degradation of RAD23B-XPC complex, which is the critical factor for nucleotide excision repair to remove cisplatin-induced DNA adducts, leading to cisplatin-induced cell death. OTUD1 cleaves the K63-linked ubiquitin chain of RAD23B and XPC, and enhances PRKN mediated K48-linked ubiquitination of RAD23B-XPC and the subsequent proteasomal degradation. The findings of this study highlighted that OTUD1 could be a potential therapeutic target for NSCLC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 50","pages":"4855-4867"},"PeriodicalIF":7.3,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595396","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}
Pub Date : 2025-11-24DOI: 10.1038/s41388-025-03631-6
Yongtao Li, Zhicheng Zhou, Yiqun Zhang, Deyong Jia, Ding Wang, Mary C. Reiger, Chad J. Creighton, Peter S. Nelson, Eva Corey, Colm Morrissey, Li Xin
Wnt signaling is a complex pathway consisting of numerous ligands and frizzled (FZD) receptors. These signaling components are widely expressed in human prostate tissues and often undergo upregulation or mutation in advanced prostate cancers. Enhanced Wnt signaling promotes prostate cancer cell proliferation, metastasis, and resistance to therapy. However, targeting pan-Wnt signaling poses challenges due to tissue toxicity. We show that FZD6 is the most highly expressed and frequently amplified Wnt receptor in advanced human prostate cancers. Knockdown of FZD6 suppresses both in vitro and in vivo growth of various prostate cancer cell lines and patient-derived xenograft models. FZD6 knockdown impairs DNA double-strand break (DSB) repair, as determined by both resolution of γH2AX foci and DNA DSB repair reporter assays. Mechanistically, FZD6 knockdown-induced growth suppression is linked to reduced activities of SRC kinase and STAT3, while DNA damage repair deficiency is mediated through WEE1 downregulation via PLK1. Knockdown of FZD6 enhances the therapeutic efficacy of genotoxic agents for prostate cancer cells. A kinome-wide CRISPR-Cas9 knockout screen reveals that FZD6 inhibition sensitizes prostate cancer cells to the inhibition of PKMYT1, a WEE kinase family member. Collectively, we demonstrate that targeting a single FZD receptor highly expressed in prostate cancers can yield significant therapeutic efficacy, and uncover therapeutic vulnerabilities associated with FZD6 inhibition.
{"title":"Targeting FZD6 creates therapeutically actionable vulnerabilities for advanced prostate cancer","authors":"Yongtao Li, Zhicheng Zhou, Yiqun Zhang, Deyong Jia, Ding Wang, Mary C. Reiger, Chad J. Creighton, Peter S. Nelson, Eva Corey, Colm Morrissey, Li Xin","doi":"10.1038/s41388-025-03631-6","DOIUrl":"10.1038/s41388-025-03631-6","url":null,"abstract":"Wnt signaling is a complex pathway consisting of numerous ligands and frizzled (FZD) receptors. These signaling components are widely expressed in human prostate tissues and often undergo upregulation or mutation in advanced prostate cancers. Enhanced Wnt signaling promotes prostate cancer cell proliferation, metastasis, and resistance to therapy. However, targeting pan-Wnt signaling poses challenges due to tissue toxicity. We show that FZD6 is the most highly expressed and frequently amplified Wnt receptor in advanced human prostate cancers. Knockdown of FZD6 suppresses both in vitro and in vivo growth of various prostate cancer cell lines and patient-derived xenograft models. FZD6 knockdown impairs DNA double-strand break (DSB) repair, as determined by both resolution of γH2AX foci and DNA DSB repair reporter assays. Mechanistically, FZD6 knockdown-induced growth suppression is linked to reduced activities of SRC kinase and STAT3, while DNA damage repair deficiency is mediated through WEE1 downregulation via PLK1. Knockdown of FZD6 enhances the therapeutic efficacy of genotoxic agents for prostate cancer cells. A kinome-wide CRISPR-Cas9 knockout screen reveals that FZD6 inhibition sensitizes prostate cancer cells to the inhibition of PKMYT1, a WEE kinase family member. Collectively, we demonstrate that targeting a single FZD receptor highly expressed in prostate cancers can yield significant therapeutic efficacy, and uncover therapeutic vulnerabilities associated with FZD6 inhibition.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 50","pages":"4868-4877"},"PeriodicalIF":7.3,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03631-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1038/s41388-025-03646-z
Wei Ding, Zihan Ding, Qinghong Zeng, Yan Qiu, Christopher R. Donnelly, Yuqi Wu, Yuchen Jiang, Qi Han, Hao Xu, Hao Cui, Xiangfei Liu, Xin Chen, Sixin Jiang, Mei Huang, Dan Pan, Dan Yang, Li Li, Lihong Yao, Minghai Tang, Jing Li, Taiwen Li, Xiaoping Xu, Qianming Chen, Hang Zhao, Longyu Li, Lu Jiang, Xiaobo Luo
Early intervention of precancers is significant for improving cancer outcome. EZH2-mediated epigenetic modification was responsible for the immune escape of cancers; besides, tumor immune evasion is correlated with the impaired MHC-I antigen presentation machinery (APM). Oral potentially malignant disorders (OPMDs), represented by oral leukoplakia (OLK), usually precede head and neck squamous cell carcinoma (HNSCC). EZH2 is correlated with malignant transformation (MT) of OPMDs including OLK, while it remains undetermined that whether EZH2 mediates the initiation of HNSCC by repressing APM. Herein, EZH2 was first reported to negatively correlate with MHC-I and CD8+ GZMB+ T subsets which promote antitumor immunity in OPMDs. In vitro study uncovered that EZH2 triggers H3K27me3 on the promoters of MHC-I associated genes such as HLA-A/B/C, B2M and TAP1. Next, we constructed one hydrogel loaded with GSK126, a specific EZH2 inhibitor, denoted as PPT@GSK126 which is well-tolerated and highly adhesive to mucosa. Preclinical trials demonstrated that topical PPT@GSK126 could significantly prevent the MT of OPMDs and induce robust specific immune killing of dysplastic cells; while individual local αPD-1 therapy was unavailable, PPT@GSK126 synergized with topical αPD-1 therapy to significantly repress the cancerization of OPMDs. As EZH2 is highly expressed in numerous precancers, PPT@GSK126 has broad application prospects for reducing these tumor burdens.
{"title":"Prevention of cancer initiation by augmenting MHC-I antigen presentation via EZH2 inhibition","authors":"Wei Ding, Zihan Ding, Qinghong Zeng, Yan Qiu, Christopher R. Donnelly, Yuqi Wu, Yuchen Jiang, Qi Han, Hao Xu, Hao Cui, Xiangfei Liu, Xin Chen, Sixin Jiang, Mei Huang, Dan Pan, Dan Yang, Li Li, Lihong Yao, Minghai Tang, Jing Li, Taiwen Li, Xiaoping Xu, Qianming Chen, Hang Zhao, Longyu Li, Lu Jiang, Xiaobo Luo","doi":"10.1038/s41388-025-03646-z","DOIUrl":"10.1038/s41388-025-03646-z","url":null,"abstract":"Early intervention of precancers is significant for improving cancer outcome. EZH2-mediated epigenetic modification was responsible for the immune escape of cancers; besides, tumor immune evasion is correlated with the impaired MHC-I antigen presentation machinery (APM). Oral potentially malignant disorders (OPMDs), represented by oral leukoplakia (OLK), usually precede head and neck squamous cell carcinoma (HNSCC). EZH2 is correlated with malignant transformation (MT) of OPMDs including OLK, while it remains undetermined that whether EZH2 mediates the initiation of HNSCC by repressing APM. Herein, EZH2 was first reported to negatively correlate with MHC-I and CD8+ GZMB+ T subsets which promote antitumor immunity in OPMDs. In vitro study uncovered that EZH2 triggers H3K27me3 on the promoters of MHC-I associated genes such as HLA-A/B/C, B2M and TAP1. Next, we constructed one hydrogel loaded with GSK126, a specific EZH2 inhibitor, denoted as PPT@GSK126 which is well-tolerated and highly adhesive to mucosa. Preclinical trials demonstrated that topical PPT@GSK126 could significantly prevent the MT of OPMDs and induce robust specific immune killing of dysplastic cells; while individual local αPD-1 therapy was unavailable, PPT@GSK126 synergized with topical αPD-1 therapy to significantly repress the cancerization of OPMDs. As EZH2 is highly expressed in numerous precancers, PPT@GSK126 has broad application prospects for reducing these tumor burdens.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 50","pages":"4878-4894"},"PeriodicalIF":7.3,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595395","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}
Pub Date : 2025-11-24DOI: 10.1038/s41388-025-03648-x
Justin Stebbing, George Miller
{"title":"Ten years of oncogene editorship: a decade of transformation","authors":"Justin Stebbing, George Miller","doi":"10.1038/s41388-025-03648-x","DOIUrl":"10.1038/s41388-025-03648-x","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 50","pages":"4833-4834"},"PeriodicalIF":7.3,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03648-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Damage-associated molecular patterns (DAMPs) are secreted from damaged or dying cells and activate innate immune signaling via pattern-recognition receptors such as Toll-like receptors and cGAS. We previously showed that topotecan, a chemotherapeutic drug and topoisomerase I (TOP1) inhibitor, binds to ribosomal protein RPL15 and induces the secretion of DAMPs from cancer cells, which activate cGAS-STING signaling in dendritic cells. RPL15-knockdown B16-F10 melanoma tumors were sensitized to anti-PD-1 antibody, suggesting that RPL15 inhibition may have the potential to improve immune checkpoint inhibitor efficacy. However, topotecan and its derivatives, including SN-38, are highly cytotoxic because of their TOP1 inhibitory activity. Here, we synthesized SN-38-conjugated pomalidomide (SN38-PROTAC) and showed that SN38-PROTAC induced ubiquitin-mediated degradation of RPL15, but not TOP1. SN38-PROTAC treatment induced DAMP secretion from cancer cells, which activated cGAS-STING signaling in dendritic cells. The cytotoxicity of SN38-PROTAC in MCF7 cells was 100-fold lower than SN-38. SN38-PROTAC treatment increased the CTL/Treg ratio in tumors and sensitized B16-F10 tumors to anti-PD-1 antibody in a mouse model. The enhanced antitumor effects of SN38-PROTAC and anti-PD-1 antibody combination were abolished in STING-deficient mice. Our results indicate that SN38-PROTAC, which induces RPL15 degradation, has the potential to enhance ICI efficacy in PD-1-resistant cancer with low cytotoxicity.
{"title":"A selective RPL15 PROTAC degrader enhances anti-PD-1 immunotherapy in a murine melanoma tumor model","authors":"Runa Takahashi, Kazuki Yamamoto, Hikaru Toya, Haruka Shoji, Kohei Kawanishi, Kyoka Momosaki, Miyuki Yabe, Ken Takashima, Ryuta Muromoto, Satoshi Ichikawa, Tadashi Matsuda, Yuichi Kitai","doi":"10.1038/s41388-025-03641-4","DOIUrl":"10.1038/s41388-025-03641-4","url":null,"abstract":"Damage-associated molecular patterns (DAMPs) are secreted from damaged or dying cells and activate innate immune signaling via pattern-recognition receptors such as Toll-like receptors and cGAS. We previously showed that topotecan, a chemotherapeutic drug and topoisomerase I (TOP1) inhibitor, binds to ribosomal protein RPL15 and induces the secretion of DAMPs from cancer cells, which activate cGAS-STING signaling in dendritic cells. RPL15-knockdown B16-F10 melanoma tumors were sensitized to anti-PD-1 antibody, suggesting that RPL15 inhibition may have the potential to improve immune checkpoint inhibitor efficacy. However, topotecan and its derivatives, including SN-38, are highly cytotoxic because of their TOP1 inhibitory activity. Here, we synthesized SN-38-conjugated pomalidomide (SN38-PROTAC) and showed that SN38-PROTAC induced ubiquitin-mediated degradation of RPL15, but not TOP1. SN38-PROTAC treatment induced DAMP secretion from cancer cells, which activated cGAS-STING signaling in dendritic cells. The cytotoxicity of SN38-PROTAC in MCF7 cells was 100-fold lower than SN-38. SN38-PROTAC treatment increased the CTL/Treg ratio in tumors and sensitized B16-F10 tumors to anti-PD-1 antibody in a mouse model. The enhanced antitumor effects of SN38-PROTAC and anti-PD-1 antibody combination were abolished in STING-deficient mice. Our results indicate that SN38-PROTAC, which induces RPL15 degradation, has the potential to enhance ICI efficacy in PD-1-resistant cancer with low cytotoxicity.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 50","pages":"4846-4854"},"PeriodicalIF":7.3,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03641-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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