Cancer discovery最新文献

{"title":"Antitumor activity of vebreltinib and characterization of clinicogenomic features in solid tumors with MET rearrangements.","authors":"Seshiru Nakazawa, Federica Pecci, Igor Odintsov, Dimitris Gazgalis, Felix H Gottlieb, Biagio Ricciuti, Lodovica Zullo, Joao V Alessi, Alessandro Di Federico, Mihaela Aldea, Edoardo Garbo, Malini M Gandhi, Arushi Saini, William W Feng, Jie Jiang, Simon Baldacci, Francesco Facchinetti, Maisam Makarem, Marie-Anais Locquet, Koji Haratani, Danielle Haradon, Benjamin Besse, Antoine Italiano, Jordi Remon, Pernelle Lavaud, Damien Vasseur, David Planchard, Yusuke Sato, Yukako Watanabe, Scott Owen, Alexis B Cortot, Hoda Mahran, Martin D Forster, Jiaxin Niu, Pascale Tomasini, Leong Swan Swan, Kevin Tay, Emilio Esteban, Anna Minchom, Sani H Kizilbash, Marcia Cruz-Correa, Kin-Hung Peony Yu, Xiaoling Zhang, Pan Chen, Mythili Sangem, Jianwei Che, Lynette M Sholl, Pasi A Janne, Mark M Awad","doi":"10.1158/2159-8290.CD-24-1726","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1726","url":null,"abstract":"<p><p>Oncogenic translocations involving the MET gene have been reported in several cancer types, but detailed clinicogenomic characterization of these cancers is not well defined. In addition, prospective clinical trials evaluating the antitumor activity of MET inhibitors in MET rearrangement-positive cancers are limited. Here, in a pan-cancer analysis of >46,000 solid tumors with comprehensive genomic profiling, we identified oncogenic MET rearrangements in ~0.04% of cancers. Preliminary analysis from a phase 2 clinical trial of the type I MET tyrosine kinase inhibitor (TKI) vebreltinib in MET fusion-positive solid tumors demonstrated an objective response rate of 50% and disease control rate of 79%, with antitumor activity seen in diverse cancer types including lung adenocarcinoma, intrahepatic cholangiocarcinoma, among others. Similar to MET exon 14-altered lung cancer, secondary mutations in the kinase domain can confer resistance to MET TKIs in MET fusion-positive cancers. Overall, these data categorize MET rearrangements as actionable targets in solid tumors.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810522","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":"Convergent Genetic Adaptation in Human Tumors Developed Under Systemic Hypoxia and in Populations Living at High Altitudes","authors":"Carlota Arenillas, Lucía Celada, José Ruiz-Cantador, Bruna Calsina, Debayan Datta, Eduardo García-Galea, Roberta Fasani, Ana Belén Moreno-Cárdenas, Juan José Alba-Linares, Berta Miranda-Barrio, Ángel M. Martínez-Montes, Cristina Alvarez-Escola, Beatriz Lecumberri, Ana González García, Shahida K. Flores, Emmanuel Esquivel, Yanli Ding, Mirko Peitzsch, José-Ángel Robles-Guirado, Rita Maria Regojo Zapata, José Juan Pozo-Kreilinger, Carmela Iglesias, Trisha Dwight, Christopher A. Muir, Amelia Oleaga, Maria Elvira Garrido-Lestache Rodríguez-Monte, Maria Jesús Del Cerro, Isaac Martínez-Bendayán, Enol Álvarez-González, Tamara Cubiella, Delmar Muniz Lourenço, Maria Adelaide A. Pereira, Nelly Burnichon, Alexandre Buffet, Craig Broberg, Paxton V. Dickson, Mario F. Fraga, José Luis Llorente Pendás, Joaquín Rueda Soriano, Francisco Buendía Fuentes, Sergio P.A. Toledo, Roderick Clifton-Bligh, Rodrigo Dienstmann, Josep Villanueva, Jaume Capdevila, Anne-Paule Gimenez-Roqueplo, Judith Favier, Paolo Nuciforo, William F. Young, Nicole Bechmann, Alexander R. Opotowsky, Anand Vaidya, Irina Bancos, Donate Weghorn, Mercedes Robledo, Anna Casteràs, Laura Dos-Subirà, Igor Adameyko, María-Dolores Chiara, Patricia L.M. Dahia, Rodrigo A. Toledo","doi":"10.1158/2159-8290.cd-24-0943","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0943","url":null,"abstract":"This study explores parallels between systemic hypoxia adaptation in high-altitude populations and tumorigenesis. We identified EPAS1, a gene critical for hypoxia adaptation in populations such as Tibetans and Sherpas, as playing a similar adaptive role in tumors arising under hypoxic conditions. Tumors from patients with chronic hypoxia displayed impaired DNA repair and frequent emergence of EPAS1 variants, with frequencies reaching up to 90%, echoing the positive selection seen in high-altitude dwellers. Mechanistically, EPAS1 gain-of-function mutations promote COX4I2 expression, reducing cellular oxygen consumption and supporting tumor proliferation in hypoxia. Analysis of clinical data from patients with hypoxia revealed tissue-specific and time-sensitive tumorigenic effects, particularly impacting oxygen-sensitive cells in the postnatal period. Our findings suggest that EPAS1-driven adaptation mechanisms in high-altitude populations provide a model for understanding tumor evolution under hypoxic stress, highlighting how genetic adaptations to diverse stressors in natural populations may yield insights into tumorigenesis and cancer progression. Significance: This study reveals a broad convergence in genetic adaptation to hypoxia between natural populations and tumors, suggesting that insights from natural populations could enhance our understanding of cancer biology and identify novel therapeutic targets.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"25 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805772","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":"Requirement for Cyclin D1 Underlies Cell Autonomous HIF2-Dependence in Kidney Cancer.","authors":"Nitin H Shirole, Devishi Kesar, Yenarae Lee, Amy Goodale, Sudeepa Syamala, Shweta Kukreja, Rong Li, Xintao Qiu, Wenyu Yu, Seth Goldman, Paloma Cejas, Henry W Long, Karen Adelman, John G Doench, William R Sellers, William G Kaelin","doi":"10.1158/2159-8290.CD-24-1378","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1378","url":null,"abstract":"<p><p>Inactivation of the VHL gene stabilizes HIF2a, which drives clear cell renal carcinoma (ccRCC). The HIF2a inhibitor belzutifan is approved for ccRCC treatment, but de novo and acquired resistance are common. HIF2a, bound to ARNT, transcriptionally activates many genes. We performed CRISPRa screens in HIF2a-dependent ccRCC lines treated with a belzutifan analog to identify HIF2a-responsive genes that confer cell-autonomous belzutifan resistance when not downregulated. Sustaining the expression of the HIF2a target gene CCND1, encoding Cyclin D1, promoted HIF2a-independence/belzutifan resistance. This activity requires Cdk4/6 activation by Cyclin D1, but is not solely due to phosphorylation of the canonical Cyclin D1 target, pRB. Indeed, ccRCC lines lacking all three pRB family members remained at least partially HIF2a-dependent. In this context, however, a kinase-defective Cyclin D1 variant partially overrode belzutifan's antiproliferative effects, suggesting that ccRCC promotion by Cyclin D1 requires the phosphorylation of pRB paralogs and one or more kinase-independent Cyclin D1 activities.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771172","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":"Tackling Cancer through Global Team Science.","authors":"Rebecca L Eccles, Gabriela Carreno, Lorenzo de la Rica, Gemma M Balmer, David Scott","doi":"10.1158/2159-8290.CD-25-0282","DOIUrl":"10.1158/2159-8290.CD-25-0282","url":null,"abstract":"<p><p>Here, we discuss the seven new challenges set by Cancer Grand Challenges that are currently open for creative applications. We invite the research community to assemble global, interdisciplinary teams to tackle these challenges and ultimately change the way we think about, study, prevent, and treat cancer.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"673-677"},"PeriodicalIF":29.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555839","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":"The Hallmarks of Cancer as Eco-Evolutionary Processes","authors":"Ranjini Bhattacharya, Stanislav S. Avdieiev, Anuraag Bukkuri, Christopher J. Whelan, Robert A. Gatenby, Kenneth Y. Tsai, Joel S. Brown","doi":"10.1158/2159-8290.cd-24-0861","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0861","url":null,"abstract":"The “Hallmarks of Cancer” represent characteristics of neoplastic cells. Hanahan and Weinberg noted that the acquisition of these hallmarks mimics Darwinian evolution. In this study, we deconstruct the hallmarks “color wheel” into linear, parallel, and interlinked stages: cancer initiation, evolving evolvability, niche construction, adaptations for safety, and emergent phenomenon. During carcinogenesis, a cell evolves from being part of the organism into an autonomous unit subject to natural selection. The hallmark traits enable this transition, representing adaptations for survival within their tumor ecosystem. Unwinding the hallmarks color wheel and viewing them as eco-evolutionary processes provide a unifying framework for defining, understanding, and treating cancer. Significance: Viewing the hallmarks as a sequence of adaptations captures the “why” behind the “how” of the molecular changes driving cancer. This eco-evolutionary view distils the complexity of cancer progression into logical steps, providing a framework for understanding all existing and emerging hallmarks of cancer and developing therapeutic interventions.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"56 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757883","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":"Don’t Lose Your Nerve: Adrenergic Signaling and Bone Marrow Regeneration after Transplantation","authors":"Ravi Bhatia","doi":"10.1158/2159-8290.cd-25-0107","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0107","url":null,"abstract":"Summary: In this issue, Nishino, Hu, Kishtagari, and colleagues report that patients who receive nonselective β-blockers after allogeneic hematopoietic cell transplant exhibit delayed platelet engraftment and reduced survival. See related article by Nishino et al., p. 748","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"12 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757884","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":"Loss of p53 Induces Tolerance to Viral Mimicry as a Mechanism of Immune Evasion in Early Tumorigenesis","authors":"Takahiko Murayama, Israel Cañadas","doi":"10.1158/2159-8290.cd-25-0104","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0104","url":null,"abstract":"Summary: Ishak and colleagues report that the loss of p53 disrupts constitutive heterochromatin, enabling the transcription of immunogenic repetitive elements. Unlike acute viral mimicry activation, a chronic viral mimicry response mediated by p53 loss during cancer initiation induces tolerance to cytosolic nucleic acids, ultimately diminishing cellular immunogenicity as a strategy for immune evasion. See related article by Ishak et al., p. 793","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"24 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757882","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":"Connections across the Cancer Continuum.","authors":"Luis A Diaz, Lewis C Cantley","doi":"10.1158/2159-8290.CD-25-0210","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-25-0210","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 4","pages":"663"},"PeriodicalIF":29.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762917","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":"Correction: DNAJB1-PRKACA Fusion Drives Fibrolamellar Liver Cancer through Impaired SIK Signaling and CRTC2/p300-Mediated Transcriptional Reprogramming.","authors":"Ilaria Gritti, Jinkai Wan, Vajira Weeresekara, Joel M Vaz, Giuseppe Tarantino, Tenna Holgersen Bryde, Vindhya Vijay, Ashwin V Kammula, Prabhat Kattel, Songli Zhu, Phuong Vu, Marina Chan, Meng-Ju Wu, John D Gordan, Krushna C Patra, Vanessa S Silveira, Robert T Manguso, Marc N Wein, Christopher J Ott, Jun Qi, David Liu, Kei Sakamoto, Taranjit S Gujral, Nabeel Bardeesy","doi":"10.1158/2159-8290.CD-25-0298","DOIUrl":"10.1158/2159-8290.CD-25-0298","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 4","pages":"862"},"PeriodicalIF":29.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11962388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762919","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}

{"title":"Insights on Future Directions in Cancer Research from the 2025 AACR NextGen Stars.","authors":"Edmond M Chan, Yash Chhabra, Karen O Dixon, Adam D Durbin, Anniina Färkkilä, Anand D Jeyasekharan, Zuzana Keckesova, John R Prensner, Elvin Wagenblast, Stephanie Z Xie, Di Zhao","doi":"10.1158/2159-8290.CD-25-0239","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-25-0239","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 4","pages":"678-684"},"PeriodicalIF":29.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762921","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}