Cancer research最新文献_第2页

Targeting Fatty Acid Metabolism Abrogates the Differentiation Blockade in Pre-leukemic Cells 以脂肪酸代谢为靶点可减轻白血病前期细胞的分化障碍

IF 11.2 1区医学

Cancer research Pub Date : 2024-09-12 DOI: 10.1158/0008-5472.can-23-3861

Xiaoyu Liu, Yu Liu, Qing Rao, Yihan Mei, Haiyan Xing, Runxia Gu, Junli Mou, Manling Chen, Fan Ding, Wanqing Xie, Kejing Tang, Zheng Tian, Min Wang, Shaowei Qiu, Jianxiang Wang

{"title":"Targeting Fatty Acid Metabolism Abrogates the Differentiation Blockade in Pre-leukemic Cells","authors":"Xiaoyu Liu, Yu Liu, Qing Rao, Yihan Mei, Haiyan Xing, Runxia Gu, Junli Mou, Manling Chen, Fan Ding, Wanqing Xie, Kejing Tang, Zheng Tian, Min Wang, Shaowei Qiu, Jianxiang Wang","doi":"10.1158/0008-5472.can-23-3861","DOIUrl":"https://doi.org/10.1158/0008-5472.can-23-3861","url":null,"abstract":"Metabolism plays a key role in the maintenance of normal hematopoietic stem cells (HSCs) and in the development of leukemia. A better understanding of the metabolic characteristics and dependencies of pre-leukemic cells could help identify potential therapeutic targets to prevent leukemic transformation. As AML1-ETO, one of the most frequent fusion proteins in acute myeloid leukemia that is encoded by a RUNX1::RUNX1T1 fusion gene, is capable of generating pre-leukemic clones, here we used a conditional Runx1::Runx1t1 knock-in mouse model to evaluate pre-leukemic cell metabolism. AML1-ETO expression resulted in impaired hematopoietic reconstitution and increased self-renewal ability. Oxidative phosphorylation and glycolysis decreased significantly in these pre-leukemic cells accompanied by increased HSC quiescence and reduced cell cycling. Furthermore, HSCs expressing AML1-ETO exhibited an increased requirement for fatty acids through metabolic flux. Dietary lipid deprivation or loss of the fatty acid transporter FATP3 by targeted deletion using CRISPR/Cas9 partially restored differentiation. These findings reveal the unique metabolic profile of pre-leukemic cells and propose FATP3 as a potential target for disrupting leukemogenesis.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174960","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}

引用次数: 0

Cancer-Associated Fibroblasts Expressing Sulfatase 1 Facilitate VEGFA-Dependent Microenvironmental Remodeling to Support Colorectal Cancer 表达硫酸化酶 1 的癌症相关成纤维细胞促进血管内皮生长因子依赖性微环境重塑，为结直肠癌提供支持

IF 11.2 1区医学

Cancer research Pub Date : 2024-09-09 DOI: 10.1158/0008-5472.can-23-3987

Huijuan Wang, Jiaxin Chen, Xiaoyu Chen, Yingqiang Liu, Jiawei Wang, Qing Meng, Huogang Wang, Ying He, Yujia Song, Jingyun Li, Zhenyu Ju, Peng Xiao, Junbin Qian, Zhangfa Song

{"title":"Cancer-Associated Fibroblasts Expressing Sulfatase 1 Facilitate VEGFA-Dependent Microenvironmental Remodeling to Support Colorectal Cancer","authors":"Huijuan Wang, Jiaxin Chen, Xiaoyu Chen, Yingqiang Liu, Jiawei Wang, Qing Meng, Huogang Wang, Ying He, Yujia Song, Jingyun Li, Zhenyu Ju, Peng Xiao, Junbin Qian, Zhangfa Song","doi":"10.1158/0008-5472.can-23-3987","DOIUrl":"https://doi.org/10.1158/0008-5472.can-23-3987","url":null,"abstract":"Tumor stroma plays a critical role in fostering tumor progression and metastasis. Cancer-associated fibroblasts (CAFs) are a major component of the tumor stroma. Identifying the key molecular determinants for the pro-tumor properties of CAFs could enable the development of more effective treatment strategies. Herein, through analyses of single-cell sequencing data, we identified a population of CAFs expressing high levels of sulfatase 1 (SULF1), which was associated with poor prognosis in colorectal cancer (CRC) patients. CRC models using mice with conditional SULF1 knockout in fibroblasts revealed the tumor-supportive function of SULF1+ CAFs. Mechanistically, SULF1+ CAFs enhanced the release of vascular endothelial growth factor A (VEGFA) from heparan sulfate proteoglycan (HSPG). The increased bioavailability of VEGFA initiated the deposition of extracellular matrix (ECM) and enhanced angiogenesis. In addition, intestinal microbiota-produced butyrate suppressed SULF1 expression in CAFs through its HDAC inhibitory activity. The insufficient butyrate production in CRC patients increased the abundance of SULF1+ CAFs, thereby promoting tumor progression. Importantly, tumor growth inhibition by HDAC inhibition was dependent on SULF1 expression in CAFs, and CRC patients with more SULF1+ CAFs were more responsive to treatment with the HDAC inhibitor chidamide. Collectively, these findings unveil the critical role of SULF1+ CAFs in CRC and provide a strategy to stratify CRC patients for HDAC inhibitor treatment.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160523","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}

引用次数: 0

Targeting NTRK1 Enhances Immune Checkpoint Inhibitor Efficacy in NTRK1 Wild-type Non-Small Cell Lung Cancer 靶向 NTRK1 可增强免疫检查点抑制剂对 NTRK1 野生型非小细胞肺癌的疗效

IF 11.2 1区医学

Cancer research Pub Date : 2024-09-09 DOI: 10.1158/0008-5472.can-24-0658

Margaret R. Smith, Caroline B. Dixon, Yuezhu Wang, Yin Liu, Ralph D’Agostino, Jimmy Ruiz, George Oliver, Lance D. Miller, Umit Topaloglu, Michael D. Chan, Michael Farris, Jing Su, Kathryn F. Mileham, Dawen Zhao, Wencheng Li, Tammy Sexton, Thomas Lycan, Karen M. Haas, Jason M. Grayson, Fei Xing

{"title":"Targeting NTRK1 Enhances Immune Checkpoint Inhibitor Efficacy in NTRK1 Wild-type Non-Small Cell Lung Cancer","authors":"Margaret R. Smith, Caroline B. Dixon, Yuezhu Wang, Yin Liu, Ralph D’Agostino, Jimmy Ruiz, George Oliver, Lance D. Miller, Umit Topaloglu, Michael D. Chan, Michael Farris, Jing Su, Kathryn F. Mileham, Dawen Zhao, Wencheng Li, Tammy Sexton, Thomas Lycan, Karen M. Haas, Jason M. Grayson, Fei Xing","doi":"10.1158/0008-5472.can-24-0658","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0658","url":null,"abstract":"Treatment of non-small cell lung cancer (NSCLC) has drastically changed in recent years owing to the robust anti-cancer effects of immune-checkpoint inhibitors (ICI). However, only 20% of NSCLC patients benefit from ICIs, highlighting the need to uncover the mechanisms mediating resistance. By analyzing the overall survival (OS) and mutational profiles of 424 NSCLC patients who received ICI treatments between 2015 and 2021, we determined that patients carrying a loss of function mutation in neurotrophic tyrosine kinase receptor 1 (NTRK1) had a prolonged OS compared to patients with wild-type NTRK1. Notably, suppression of the NTRK1 pathway by knockdown or Entrectinib treatment significantly enhanced ICI efficacy in mouse NSCLC models. Comprehensive T cell population analyses demonstrated that stem-like CD4+ T cells and effector CD4+ and CD8+ T cells were highly enriched in anti-PD-1 treated mice bearing tumors with decreased NTRK1 signaling. RNA sequencing revealed that suppression of NTRK1 signaling in tumor cells increased complement C3 expression, which enhanced the recruitment of T cells and myeloid cells and stimulated M1-like macrophage polarization in the tumor. Together, this study demonstrates a role for NTRK1 signaling in regulating crosstalk between tumor cells and immune cells in the tumor microenvironment and provides a potential therapeutic approach to overcomes immunotherapy resistance in NTRK1 wild-type NSCLC patients.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160522","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}

引用次数: 0

B7-H3-Targeted CAR-Vδ1T Cells Exhibit Potent Broad-Spectrum Activity Against Solid Tumors. B7-H3靶向CAR-Vδ1T细胞对实体瘤具有强效广谱活性

IF 12.5 1区医学

Cancer research Pub Date : 2024-09-06 DOI: 10.1158/0008-5472.CAN-24-0195

Licui Jiang, Fengtao You, Hai Wu, Changsong Qi, Shufen Xiang, Ping Zhang, Huimin Meng, Min Wang, Jiequn Huang, Yafen Li, Dan Chen, Gangli An, Nan Yang, Bozhen Zhang, Lin Shen, Lin Yang

{"title":"B7-H3-Targeted CAR-Vδ1T Cells Exhibit Potent Broad-Spectrum Activity Against Solid Tumors.","authors":"Licui Jiang, Fengtao You, Hai Wu, Changsong Qi, Shufen Xiang, Ping Zhang, Huimin Meng, Min Wang, Jiequn Huang, Yafen Li, Dan Chen, Gangli An, Nan Yang, Bozhen Zhang, Lin Shen, Lin Yang","doi":"10.1158/0008-5472.CAN-24-0195","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-0195","url":null,"abstract":"Vδ1T cells, a rare subset of γδT cells, hold promise for treating solid tumors. Unlike conventional T cells, they recognize tumor antigens independently of the MHC antigen-presentation pathway, making them a potential \"off-the-shelf\" cell therapy product. However, isolation and activation of Vδ1T cells is challenging, which has limited their clinical investigation. Here, we developed a large-scale clinical-grade manufacturing process for Vδ1T cells and validated the therapeutic potential of B7-H3-CAR-modified Vδ1T cells in treating solid tumors. Co-expression of interleukin-2 with the B7-H3-CAR led to durable anti-tumor activity of Vδ1T cells in vitro and in vivo. In multiple subcutaneous and orthotopic mouse xenograft tumor models, a single intravenous administration of the CAR-Vδ1T cells resulted in complete tumor regression. These modified cells demonstrated significant in vivo expansion and robust homing ability to tumors, akin to natural tissue-resident immune cells. Additionally, the B7-H3-CAR-Vδ1T cells exhibited a favorable safety profile. In conclusion, B7-H3-CAR-modified Vδ1T cells represent a promising strategy for treating solid tumors.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143028","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}

引用次数: 0

MYC Drives mRNA Pseudouridylation to Mitigate Proliferation-Induced Cellular Stress during Cancer Development. MYC 驱动 mRNA 伪酸化，以减轻癌症发展过程中增殖诱导的细胞压力。

IF 12.5 1区医学

Cancer research Pub Date : 2024-09-06 DOI: 10.1158/0008-5472.CAN-24-1102

Jane Ding, Mohit Bansal, Yuxia Cao, Bingwei Ye, Rui Mao, Anamika Gupta, Sunil Sudarshan, Han-Fei Ding

{"title":"MYC Drives mRNA Pseudouridylation to Mitigate Proliferation-Induced Cellular Stress during Cancer Development.","authors":"Jane Ding, Mohit Bansal, Yuxia Cao, Bingwei Ye, Rui Mao, Anamika Gupta, Sunil Sudarshan, Han-Fei Ding","doi":"10.1158/0008-5472.CAN-24-1102","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-1102","url":null,"abstract":"Pseudouridylation is a common RNA modification that is catalyzed by the family of pseudouridine synthases (PUS). Pseudouridylation can increase RNA stability and rigidity, thereby impacting RNA splicing, processing, and translation. Given that RNA metabolism is frequently altered in cancer, pseudouridylation may be a functionally important process in tumor biology. Here, we showed that the MYC family of oncoproteins transcriptionally upregulates PUS7 expression during cancer development. PUS7 was essential for the growth and survival of MYC-driven cancer cells and xenografts by promoting adaptive stress responses and amino acid biosynthesis and import. ATF4, a master regulator of stress responses and cellular metabolism, was identified as a key downstream mediator of PUS7 functional activity. Induction of ATF4 by MYC oncoproteins and cellular stress required PUS7, and ATF4 overexpression overcame the growth inhibition caused by PUS7 deficiency. Mechanistically, PUS7 induced pseudouridylation of MCTS1 mRNA, which enhanced its translation. MCTS1, a noncanonical translation initiation factor, drove stress-induced ATF4 protein expression. A PUS7 consensus pseudouridylation site in the 3' untranslated region of ATF4 mRNA was crucial for the induction of ATF4 by cellular stress. These findings unveil a MYC-activated mRNA pseudouridylation program that mitigates cellular stress induced by MYC stimulation of proliferation and biomass production, suggesting that targeting PUS7 could be therapeutic strategy selectively against MYC-driven cancers.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143029","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}

引用次数: 0

The Pan-tumor Vasculature Under the Transcriptomic Magnifying Glass. 转录组放大镜下的泛肿瘤血管

IF 12.5 1区医学

Cancer research Pub Date : 2024-09-06 DOI: 10.1158/0008-5472.CAN-24-3219

Krish Skandha Gopalan, Gabriele Bergers

{"title":"The Pan-tumor Vasculature Under the Transcriptomic Magnifying Glass.","authors":"Krish Skandha Gopalan, Gabriele Bergers","doi":"10.1158/0008-5472.CAN-24-3219","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-3219","url":null,"abstract":"In the first pan-cancer analysis of the tumor vasculature, Pan and colleagues profile nearly 200,000 endothelial and mural cells (ECs and MCs), identifying novel subclusters and cell states using consensus trajectory inference. They identify differentiation trajectories in vascular and lymphatic endothelial cells, and subtype the pericyte population. During sprouting angiogenesis, venous cells dedifferentiate and transition to capillary and, finally, arterial ECs. Capillary ECs transition via \"three angiogenic stages\" (SI-SIII) during which APLN+ TipS1 cells were identified as potential modulators of tumor-induced neovascularization and anti-angiogenic therapy response. In lymphatic ECs, differentiation was inversely correlated between the lymphangiogenic (T1) and antigen-presenting (T2) trajectories, with T2 associated with a better prognosis. While several pericyte clusters were identified, BASP1+ matrix-associated pericytes were associated with APLN+ TipS1 cells and had a worse prognosis. These findings present transcriptional validation of previous experimental findings and serve as a resource to examine the tumor vascular microenvironment in detail.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143030","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}

引用次数: 0

RUVBL1/2 Blockade Targets YTHDF1 Activity to Suppress m6A-Dependent Oncogenic Translation and Colorectal Tumorigenesis. RUVBL1/2 阻断剂靶向 YTHDF1 活性，抑制 m6A 依赖性致癌翻译和结直肠肿瘤发生。

IF 12.5 1区医学

Cancer research Pub Date : 2024-09-04 DOI: 10.1158/0008-5472.CAN-23-2081

Danyu Chen, Fenfen Ji, Qiming Zhou, Henley Cheung, Yasi Pan, Harry C-H Lau, Cong Liang, Zhenjie Yang, Pingmei Huang, Qinyao Wei, Alvin H-K Cheung, Wei Kang, Huarong Chen, Jun Yu, Chi Chun Wong

{"title":"RUVBL1/2 Blockade Targets YTHDF1 Activity to Suppress m6A-Dependent Oncogenic Translation and Colorectal Tumorigenesis.","authors":"Danyu Chen, Fenfen Ji, Qiming Zhou, Henley Cheung, Yasi Pan, Harry C-H Lau, Cong Liang, Zhenjie Yang, Pingmei Huang, Qinyao Wei, Alvin H-K Cheung, Wei Kang, Huarong Chen, Jun Yu, Chi Chun Wong","doi":"10.1158/0008-5472.CAN-23-2081","DOIUrl":"10.1158/0008-5472.CAN-23-2081","url":null,"abstract":"The N6-methyladenosine (m6A) RNA-binding protein YTHDF1 is frequently overexpressed in colorectal cancer and drives chemotherapeutic resistance. To systematically identify druggable targets in colorectal cancer with high expression of YTHDF1, this study used a CRISPR/Cas9 screening strategy that revealed RUVBL1 and RUVBL2 as putative targets. RUVBL1/2 were overexpressed in primary colorectal cancer samples and represented independent predictors of poor patient prognosis. Functionally, loss of RUVBL1/2 preferentially impaired the growth of YTHDF1-high colorectal cancer cells, patient-derived primary colorectal cancer organoids, and subcutaneous xenografts. Mechanistically, YTHFD1 and RUVBL1/2 formed a positive feedforward circuit to accelerate oncogenic translation. YTHDF1 bound to m6A-modified RUVBL1/2 mRNA to promote translation initiation and protein expression. Coimmunoprecipitation and mass spectrometry identified that RUVBL1/2 reciprocally interacted with YTHDF1 at 40S translation initiation complexes. Consequently, RUVBL1/2 depletion stalled YTHDF1-driven oncogenic translation and nascent protein biosynthesis, leading to proliferative arrest and apoptosis. Ribosome sequencing revealed that RUVBL1/2 loss impaired the activation of MAPK, RAS, and PI3K-AKT signaling induced by YTHDF1. Finally, the blockade of RUVBL1/2 by the pharmacological inhibitor CB6644 or vesicle-like nanoparticle-encapsulated siRNAs preferentially arrested the growth of YTHDF1-expressing colorectal cancer in vitro and in vivo. Our findings show that RUVBL1/2 are potential prognostic markers and druggable targets that regulate protein translation in YTHDF1-high colorectal cancer. Significance: RUVBL1/2 inhibition is a therapeutic strategy to abrogate YTHDF1-driven oncogenic translation and overcome m6A dysregulation in colorectal cancer.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11372367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141431484","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}

引用次数: 0

Retraction: Collagen Prolyl Hydroxylases Are Essential for Breast Cancer Metastasis. 撤回：胶原脯氨酰羟化酶对乳腺癌转移至关重要

IF 12.5 1区医学

Cancer research Pub Date : 2024-09-04 DOI: 10.1158/0008-5472.CAN-24-2214

Daniele M Gilkes, Pallavi Chaturvedi, Saumendra Bajpai, Carmen C Wong, Hong Wei, Stephen Pitcairn, Maimon E Hubbi, Denis Wirtz, Gregg L Semenza

引用次数: 0

Retraction: PHGDH Expression Is Required for Mitochondrial Redox Homeostasis, Breast Cancer Stem Cell Maintenance, and Lung Metastasis. 撤回：线粒体氧化还原稳态、乳腺癌干细胞维持和肺转移需要 PHGDH 的表达

IF 12.5 1区医学

Cancer research Pub Date : 2024-09-04 DOI: 10.1158/0008-5472.CAN-24-2215

Debangshu Samanta, Youngrok Park, Shaida A Andrabi, Laura M Shelton, Daniele M Gilkes, Gregg L Semenza

引用次数: 0

PRKDC Induces Chemoresistance in Osteosarcoma by Recruiting GDE2 to Stabilize GNAS and Activate AKT. PRKDC 通过招募 GDE2 来稳定 GNAS 并激活 AKT，从而诱导骨肉瘤的抗药性

IF 12.5 1区医学

Cancer research Pub Date : 2024-09-04 DOI: 10.1158/0008-5472.CAN-24-0163

Wenchao Zhang, Wei Li, Chi Yin, Chengyao Feng, Binfeng Liu, Haodong Xu, Xin Jin, Chao Tu, Zhihong Li

{"title":"PRKDC Induces Chemoresistance in Osteosarcoma by Recruiting GDE2 to Stabilize GNAS and Activate AKT.","authors":"Wenchao Zhang, Wei Li, Chi Yin, Chengyao Feng, Binfeng Liu, Haodong Xu, Xin Jin, Chao Tu, Zhihong Li","doi":"10.1158/0008-5472.CAN-24-0163","DOIUrl":"10.1158/0008-5472.CAN-24-0163","url":null,"abstract":"Chemoresistance is one of the major causes of poor prognosis in osteosarcoma. Alternative therapeutic strategies for osteosarcoma are limited, indicating that increasing sensitivity to currently used chemotherapies could be an effective approach to improve patient outcomes. Using a kinome-wide CRISPR screen, we identified PRKDC as a critical determinant of doxorubicin (DOX) sensitivity in osteosarcoma. The analysis of clinical samples demonstrated that PRKDC was hyperactivated in osteosarcoma, and functional experiments showed that the loss of PRKDC significantly increased sensitivity of osteosarcoma to DOX. Mechanistically, PRKDC recruited and bound GDE2 to enhance the stability of protein GNAS. The elevated GNAS protein levels subsequently activated AKT phosphorylation and conferred resistance to DOX. The PRKDC inhibitor AZD7648 and DOX synergized and strongly suppressed the growth of osteosarcoma in mouse xenograft models and human organoids. In conclusion, the PRKDC-GDE2-GNAS-AKT regulatory axis suppresses DOX sensitivity and comprises targetable candidates for improving the efficacy of chemotherapy in osteosarcoma. Significance: Targeting PRKDC suppresses AKT activation and increases sensitivity to doxorubicin in osteosarcoma, which provides a therapeutic strategy for overcoming chemoresistance.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11372366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141431482","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}

引用次数: 0