Cancer discovery最新文献

{"title":"Zongertinib (BI 1810631), an Irreversible HER2 TKI, Spares EGFR Signaling and Improves Therapeutic Response in Preclinical Models and Patients with HER2-Driven Cancers.","authors":"Birgit Wilding, Lydia Woelflingseder, Anke Baum, Krzysztof Chylinski, Gintautas Vainorius, Neil Gibson, Irene C Waizenegger, Daniel Gerlach, Martin Augsten, Fiona Spreitzer, Yukina Shirai, Masachika Ikegami, Sylvia Tilandyová, Dirk Scharn, Mark A Pearson, Johannes Popow, Anna C Obenauf, Noboru Yamamoto, Shunsuke Kondo, Frans L Opdam, Annemarie Bruining, Shinji Kohsaka, Norbert Kraut, John V Heymach, Flavio Solca, Ralph A Neumüller","doi":"10.1158/2159-8290.CD-24-0306","DOIUrl":"10.1158/2159-8290.CD-24-0306","url":null,"abstract":"<p><p>Mutations in ERBB2 (encoding HER2) occur in 2% to 4% of non-small cell lung cancer (NSCLC) and confer poor prognosis. ERBB-targeting tyrosine kinase inhibitors, approved for treating other HER2-dependent cancers, are ineffective in HER2-mutant NSCLC due to dose-limiting toxicities or suboptimal potency. We report the discovery of zongertinib (BI 1810631), a covalent HER2 inhibitor. Zongertinib potently and selectively blocks HER2, while sparing EGFR, and inhibits the growth of cells dependent on HER2 oncogenic driver events, including HER2-dependent human cancer cells resistant to trastuzumab deruxtecan. Zongertinib displays potent antitumor activity in HER2-dependent human NSCLC xenograft models and enhances the activities of antibody-drug conjugates and KRASG12C inhibitors without causing obvious toxicities. The preclinical efficacy of zongertinib translates in objective responses in patients with HER2-dependent tumors, including cholangiocarcinoma (SDC4-NRG1 fusion) and breast cancer (V777L HER2 mutation), thus supporting the ongoing clinical development of zongertinib. Significance: HER2-mutant NSCLC poses a challenge in the clinic due to limited options for targeted therapies. Pan-ERBB blockers are limited by wild-type EGFR-mediated toxicity. Zongertinib is a highly potent and wild-type EGFR-sparing HER2 inhibitor that is active in HER2-driven tumors in the preclinical and clinical settings.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"119-138"},"PeriodicalIF":29.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153172","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":"Cancer Research in the Age of Spatial Omics: Lessons from IMAXT.","authors":"Dario Bressan, Nicholas Walton, Gregory J Hannon","doi":"10.1158/2159-8290.CD-24-1686","DOIUrl":"10.1158/2159-8290.CD-24-1686","url":null,"abstract":"<p><p>The Imaging and Molecular Annotation of Xenografts and Tumors Cancer Grand Challenges team was set up with the objective of developing the \"next generation\" of pathology and cancer research by using a combination of single-cell and spatial omics tools to produce 3D molecularly annotated maps of tumors. Its activities overlapped, and in some cases catalyzed, a spatial revolution in biology that saw new technologies being deployed to investigate the roles of tumor heterogeneity and of the tumor micro-environment. See related article by Stratton et al., p. 22 See related article by Bhattacharjee et al., p. 28 See related article by Goodwin et al., p. 34.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 1","pages":"16-21"},"PeriodicalIF":29.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969744","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: The 3D Revolution in Cancer Discovery.","authors":"Linghua Wang, Mingyao Li, Tae Hyun Hwang","doi":"10.1158/2159-8290.CD-24-1776","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1776","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 1","pages":"245"},"PeriodicalIF":29.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969746","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":"Combined KRAS Inhibition and Immune Therapy Generates Durable Complete Responses in an Autochthonous PDAC Model.","authors":"Yonghong Liu, Jincheng Han, Wen-Hao Hsu, Kyle A LaBella, Pingna Deng, Xiaoying Shang, Paulino Tallón de Lara, Li Cai, Shan Jiang, Ronald A DePinho","doi":"10.1158/2159-8290.CD-24-0489","DOIUrl":"10.1158/2159-8290.CD-24-0489","url":null,"abstract":"<p><strong>Significance: </strong>Clinically available KRAS* inhibitors and IO agents alleviated the immunosuppressive tumor microenvironment in PDAC. Profound tumor regression and prolonged survival in an autochthonous PDAC model provide a compelling rationale for combining KRAS* inhibition with IO agents targeting multiple arms of the immunity cycle to combat PDAC.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"162-178"},"PeriodicalIF":29.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342164","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":"Chromothripsis-Mediated Small Cell Lung Carcinoma.","authors":"Natasha Rekhtman, Sam E Tischfield, Christopher A Febres-Aldana, Jake June-Koo Lee, Jason C Chang, Benjamin O Herzberg, Pier Selenica, Hyung Jun Woo, Chad M Vanderbilt, Soo-Ryum Yang, Fei Xu, Anita S Bowman, Edaise M da Silva, Anne Marie Noronha, Diana L Mandelker, Miika Mehine, Semanti Mukherjee, Juan Blanco-Heredia, John J Orgera, Gouri J Nanjangud, Marina K Baine, Rania G Aly, Jennifer L Sauter, William D Travis, Omid Savari, Andre L Moreira, Christina J Falcon, Francis M Bodd, Christina E Wilson, Jacklynn V Sienty, Parvathy Manoj, Harsha Sridhar, Lu Wang, Noura J Choudhury, Michael Offin, Helena A Yu, Alvaro Quintanal-Villalonga, Michael F Berger, Marc Ladanyi, Mark T A Donoghue, Jorge S Reis-Filho, Charles M Rudin","doi":"10.1158/2159-8290.CD-24-0286","DOIUrl":"10.1158/2159-8290.CD-24-0286","url":null,"abstract":"<p><p>Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. Here, we performed detailed clinicopathologic, genomic, and transcriptomic profiling of an atypical subset of SCLC that lacked RB1 and TP53 co-inactivation and arose in never/light smokers. We found that most cases were associated with chromothripsis-massive, localized chromosome shattering-recurrently involving chromosome 11 or 12 and resulting in extrachromosomal amplification of CCND1 or co-amplification of CCND2/CDK4/MDM2, respectively. Uniquely, these clinically aggressive tumors exhibited genomic and pathologic links to pulmonary carcinoids, suggesting a previously uncharacterized mode of SCLC pathogenesis via transformation from lower-grade neuroendocrine tumors or their progenitors. Conversely, SCLC in never-smokers harboring inactivated RB1 and TP53 exhibited hallmarks of adenocarcinoma-to-SCLC derivation, supporting two distinct pathways of plasticity-mediated pathogenesis of SCLC in never-smokers. Significance: Here, we provide the first detailed description of a unique SCLC subset lacking RB1/TP53 alterations and identify extensive chromothripsis and pathogenetic links to pulmonary carcinoids as its hallmark features. This work defines atypical SCLC as a novel entity among lung cancers, highlighting its exceptional histogenesis, clinicopathologic characteristics, and therapeutic vulnerabilities. See related commentary by Nadeem and Drapkin, p. 8.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"83-104"},"PeriodicalIF":29.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055042","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":"Visualizing Cancer Heterogeneity at the Molecular and Cellular Levels: Lessons from Rosetta.","authors":"Richard J A Goodwin, John F Marshall, George Poulogiannis, Mariia Yuneva, Kevin M Brindle, Zoltán Takáts, Owen J Sansom, Josephine Bunch, Simon T Barry","doi":"10.1158/2159-8290.CD-24-0016","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0016","url":null,"abstract":"<p><p>Understanding tumor heterogeneity is a major challenge that was recognized as one of the first Cancer Grand Challenges, with a call to provide solutions to visualize tumor heterogeneity. The Rosetta team took on this challenge, exploiting advances in spatial-omics approaches centered around mass spectrometry imaging to map tumor heterogeneity at the cellular and molecular scales with different levels of resolution. See related article by Bressan et al., p. 16 See related article by Stratton et al., p. 22 See related article by Bhattacharjee et al., p. 28.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 1","pages":"34-38"},"PeriodicalIF":29.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969748","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":"Atypical Small Cell Lung Cancer: A New Malignancy Characterized by Chromothripsis, Carcinoid Tumors, and Wild-type RB1 and TP53.","authors":"Urooba Nadeem, Benjamin J Drapkin","doi":"10.1158/2159-8290.CD-24-1494","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1494","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) and pulmonary carcinoid tumors are traditionally seen as unrelated, with SCLC linked to smoking and characterized by biallelic loss of RB1 and TP53 and rapid progression. Rekhtman and colleagues upend these assumptions by discovering an \"atypical\" SCLC that arises in nonsmokers with intact RB1 and TP53 loci, chromothripsis-induced oncogene amplifications on extrachromosomal DNA, and frequent synchronous carcinoid tumors. See related article by Rekhtman et al., p. 83.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 1","pages":"8-10"},"PeriodicalIF":29.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969743","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":"Taking a Swing at TIMP1-Armed Immunosuppressive Astrocytes Unleashes T cell Immunity against Brain Metastases","authors":"Mihaela Lorger, Fiona James","doi":"10.1158/2159-8290.cd-24-1495","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1495","url":null,"abstract":"Summary: Priego and colleagues identify a secreted glycoprotein TIMP1, expressed downstream of the transcription factor STAT3, in a subpopulation of STAT3+ reactive astrocytes as a mediator of immunosuppression in late-stage brain metastases. The STAT3 inhibitor silibinin enhances the preclinical efficacy of the combined PD-1/CTLA4 immune checkpoint blockade, providing a rationale to translate the combination therapy into clinical use for this underserved patient group with poor prognosis. See related article by Priego et al., p. 179","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"16 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968214","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":"Implementing Mutational Epidemiology on a Global Scale: Lessons from Mutographs","authors":"Michael R. Stratton, Laura Humphreys, Ludmil B. Alexandrov, Allan Balmain, Paul Brennan, Peter J. Campbell, David H. Phillips","doi":"10.1158/2159-8290.cd-24-1687","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1687","url":null,"abstract":"Summary: The Mutographs Cancer Grand Challenge team aimed to discover unknown causes of cancer through mutational epidemiology, an alliance of cancer epidemiology and somatic genomics. By generating whole-genome sequences from thousands of cancers and normal tissues from more than 30 countries on five continents, it discovered unsuspected mutagenic exposures affecting millions of people, raised the possibility that some carcinogens act by altering forces of selection in tissue microenvironments rather than by mutagenesis, and demonstrated changes to the direction of somatic evolution in normal cells of the human body in response to exogenous exposures and noncancer diseases. See related article by Bressan et al., p. 16 See related article by Bhattacharjee et al., p. 28 See related article by Goodwin et al., p. 34","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"26 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968213","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":"Peto’s Paradox Is Dead. Long Live Peto’s Paradox","authors":"Michael J. Metzger","doi":"10.1158/2159-8290.cd-24-1539","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1539","url":null,"abstract":"Summary: In this issue, Compton and colleagues report the prevalence of neoplasia and malignant cancer in 292 species, based on 16,049 necropsy records, shedding light on susceptibility to cancer and the evolution of mechanisms that protect against cancer across a broad array of vertebrates. See related article by Compton et al., p. 227","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"49 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968215","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}