Cancer discovery最新文献

{"title":"Catalytic Inhibition of KAT6/KAT7 Enhances the Efficacy and Overcomes Primary and Acquired Resistance to Menin Inhibitors in MLL Leukemia.","authors":"Shellaina J V Gordon, Florian Perner, Laura MacPherson, Katie A Fennell, Daniela V Wenge, Wallace Bourgeois, Tabea Klaus, Thomas Plenge, Anelya Murat, Jelena Petrovic, Jakub Horvath, Joan Q Cao, John D Lapek, Sean Uryu, Jeffrey R White, Enid Y N Lam, Xinmeng Jasmine Mu, Yih-Chih Chan, Andrea Gillespie, Benjamin J Blyth, Michelle A Camerino, Ylva E Bozikis, Henrietta Holze, Kathy Knezevic, Jesse Balic, Paul A Stupple, Ian P Street, Brendon J Monahan, Shikhar Sharma, Elanor N Wainwright, Dane Vassiliadis, Thomas A Paul, Scott A Armstrong, Mark A Dawson","doi":"10.1158/2159-8290.CD-24-1517","DOIUrl":"10.1158/2159-8290.CD-24-1517","url":null,"abstract":"<p><p>Targeting MYST acetyltransferases is an exciting therapeutic opportunity in acute myeloid leukemia (AML). In this study, we define the individual and combined contribution of KAT6A, KAT6B, and KAT7 in a range of AML models, showing that although KAT6A/B inhibition is efficacious in some preclinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, markedly increases efficacy. KAT7 interacts with menin and the mixed lineage leukemia (MLL) complex and is colocalized at chromatin to coregulate oncogenic transcriptional programs. Focusing on MLL fusion oncoprotein (MLL-FP) AML, we show that inhibition of KAT6/KAT7 provides an orthogonal route to targeting menin to disable the transcriptional activity of the MLL-FP. Combined inhibition rapidly evicts the MLL-FP from chromatin, potently represses oncogenic transcription, and overcomes primary resistance to menin inhibitors. Notably, KAT7 remains an important targetable dependency in acquired genetic/nongenetic resistance to menin inhibition, providing the molecular rationale for rapid clinical translation of combination therapy, particularly in MLL-FP AML.</p><p><strong>Significance: </strong>This study provides the molecular rationale for combined targeting of KAT6/7 and menin in MLL leukemia. It reveals that combination therapy results in a rapid and profound repression of the MLL transcriptional program leading to marked differentiation and loss of leukemia-initiating capacity, setting the platform for clinical translation.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2117-2138"},"PeriodicalIF":33.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324571","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":"Germline-Somatic Liaison Dictates Cancer Subtypes via de novo Steroid Biosynthesis.","authors":"Paola Gasperini, Alessandro Alaimo, Blerta Stringa, Yoon-Mi Chung, Yari Ciani, Francesca Lorenzin, Giulia Fracassi, Yanis Zekri, Francesco Orlando, Orsetta Quaini, Sebastian Gregoricchio, Gianluca Petris, Antonio Casini, Christopher E Barbieri, Wilbert Zwart, Anna Cereseto, Nima Sharifi, Andrea Lunardi, Francesca Demichelis","doi":"10.1158/2159-8290.CD-24-1904","DOIUrl":"10.1158/2159-8290.CD-24-1904","url":null,"abstract":"<p><p>The biological mechanisms underlying the cooperation between germline genetic variants and somatic mutations during carcinogenesis are rarely elucidated. In this study, characterizing isogenic prostate cancer cell lines, we dissected the interplay between a germline variant at the 7p14.3 locus (rs1376350, G>A) and early recurrent prostate cancer-specific mutation in the speckle-type POZ protein (SPOP) gene across human prostate adenocarcinomas. The transcriptomes of multiple edited models pointed to GLI3 and the Hedgehog signaling pathway in a genotype-specific manner, whereas SPOP mutation and androgen receptor stimulation promote GLI3 accumulation in the full-length, transcriptionally active form. This, in turn, triggers the cell-autonomous production of steroids that prostate cancer relies on, in line with the enhanced responsiveness of SPOP-mutated prostate cancer to androgen deprivation therapy. These data demonstrate that germline variants dictate prostate cancer somatic evolution and suggest opportunities to jointly model germline-somatic relationship to help untangle the complexity of human cancer.</p><p><strong>Significance: </strong>Significant heritability is observed for common cancer types worldwide. The molecular mechanisms by which inherited genetics facilitate cancer initiation might transit through its cooperation with specific somatic events that then dictate the tumor features. Through a germline-somatic tandem leading to steroid biosynthesis, we suggest a paradigm to study cancer initiation.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2166-2184"},"PeriodicalIF":33.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12498101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282430","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":"Extrachromosomal DNA: A Trusted Path to Tumor Heterogeneity","authors":"Emmanuel E. Korsah, Noah A. Dusseau, Eunhee Yi","doi":"10.1158/2159-8290.cd-25-1112","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1112","url":null,"abstract":"Summary: Extrachromosomal DNA (ecDNA) has been suggested as a key factor of tumor heterogeneity at the genomic and transcriptional levels, via unequal segregation and ecDNA hub formation, respectively. In this issue of Cancer Discovery, two studies further expand our understanding of the roles of ecDNA in enhancing tumor heterogeneity at the phenotypic and spatiotemporal levels, as well as in providing a strong selective advantage during tumor evolution. See related article by Montuori et al., p. 2054 See related article by Noorani et al., p. 2078","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"77 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228970","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":"KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia.","authors":"Nicole L Michmerhuizen, Emily B Heikamp, Ilaria Iacobucci, Masayuki Umeda, Bright Arthur, Vibhor Mishra, Chun Shik Park, Danika Di Giacomo, Ryan Hiltenbrand, Qingsong Gao, Sandi Radko-Juettner, Josi Lott, Cynthia Martucci, Varsha Subramanyam, Charlie Hatton, Daniela V Wenge, Pradyuamna Baviskar, Pablo Portola, Aurelie Claquin, Bappaditya Chandra, David W Baggett, Ali Khalighifar, Hongling Huang, Peipei Zhou, Lingyun Long, Hao Shi, Yu Sun, Evangelia K Papachristou, Chandra Sekhar Reddy Chilamakuri, Francisca N de Luna Vitorino, Joanna M Gongora, Huiyun Wu, Stanley B Pounds, Laura J Janke, Alex Kentsis, Clive S D'Santos, Benjamin A Garcia, Richard W Kriwacki, Hongbo Chi, Jeffery M Klco, Scott A Armstrong, Charles G Mullighan","doi":"10.1158/2159-8290.CD-24-1772","DOIUrl":"10.1158/2159-8290.CD-24-1772","url":null,"abstract":"<p><p>NUP98 fusion oncoproteins (FO) are a hallmark of childhood acute myeloid leukemia. NUP98 FOs drive leukemogenesis through phase-separated condensate formation and maintenance of an active chromatin landscape at stem cell-associated genes in cooperation with epigenetic regulators. In this study, we show that MYST family histone acetyltransferase (HAT) complex proteins, including KAT6A/MOZ, KAT7/HBO1, and the common KAT6A/7 complex subunit BRPF1, associate with NUP98 FOs on chromatin and within condensates. MYST HATs are molecular dependencies in NUP98-rearranged (NUP98-r) leukemia, and genetic inactivation or pharmacologic inhibition of KAT6A and KAT7 impairs NUP98-r cell fitness. KAT6A/7 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, KAT6A/7 inhibition decreased leukemic burden in multiple NUP98-r leukemia xenograft mouse models, synergized with menin inhibitor treatment, and was efficacious in menin inhibitor-resistant cells. In summary, we show that MYST family HATs are therapeutically actionable dependencies in NUP98-r acute myeloid leukemia.</p><p><strong>Significance: </strong>KAT6A and KAT7 associate with NUP98 FOs to drive leukemogenesis. Inhibition of their HAT activity is an effective therapeutic strategy in NUP98-r leukemias, including those resistant to menin inhibition. Moreover, combined KAT6A/7 and menin inhibition is synergistic, supporting clinical translation to improve outcomes for NUP98 FO-driven leukemias.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2096-2116"},"PeriodicalIF":33.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12498098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324572","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":"Correction: INX-315, a Selective CDK2 Inhibitor, Induces Cell Cycle Arrest and Senescence in Solid Tumors.","authors":"Catherine Dietrich, Alec Trub, Antonio Ahn, Michael Taylor, Krutika Ambani, Keefe T Chan, Kun-Hui Lu, Christabella A Mahendra, Catherine Blyth, Rhiannon Coulson, Susanne Ramm, April C Watt, Sunil Kumar Matsa, John Bisi, Jay Strum, Patrick Roberts, Shom Goel","doi":"10.1158/2159-8290.CD-25-1502","DOIUrl":"10.1158/2159-8290.CD-25-1502","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 10","pages":"2185"},"PeriodicalIF":33.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12498096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231523","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":"Extrachromosomal DNA-Driven Oncogene Spatial Heterogeneity and Evolution in Glioblastoma.","authors":"Imran Noorani, Magnus Haughey, Jens Luebeck, Andrew Rowan, Eva Grönroos, Francesco Terenzi, Ivy Tsz-Lo Wong, Davide Pradella, Marta Lisi, Jeanette Kittel, Natasha Sharma, Chris Bailey, Clare E Weeden, Donald M Bell, Eric Joo, Vittorio Barbè, Matthew G Jones, King L Hung, Emma L Nye, Mary Green, Lucy Meader, Emma J Norton, Mark Fabian, Nnennaya Kanu, Mariam Jamal-Hanjani, Thomas Santarius, Andrea Ventura, James A R Nicoll, Delphine Boche, Howard Y Chang, Vineet Bafna, Weini Huang, Paul S Mischel, Charles Swanton, Benjamin Werner","doi":"10.1158/2159-8290.CD-24-1555","DOIUrl":"10.1158/2159-8290.CD-24-1555","url":null,"abstract":"<p><p>Oncogenes amplified on extrachromosomal DNA (ecDNA) contribute to treatment resistance and poor survival across cancers. Currently, the spatiotemporal evolution of ecDNA remains poorly understood. In this study, we integrate computational modeling with samples from 94 treatment-naive human glioblastomas (GBM) to investigate the spatiotemporal evolution of ecDNA. We observe oncogene-specific patterns of ecDNA spatial heterogeneity, emerging from random ecDNA segregation and differing fitness advantages. Unlike PDGFRA-ecDNAs, EGFR-ecDNAs often accumulate prior to clonal expansions, conferring strong fitness advantages and reaching high abundances. In corroboration, we observe pretumor ecDNA accumulation in vivo in genetically engineered mouse neural stem cells. Variant and wild-type EGFR-ecDNAs often coexist in GBM. Those variant EGFR-ecDNAs, most commonly EGFRvIII-ecDNA, always derive from preexisting wild-type EGFR-ecDNAs, occur early, and reach high abundance. Our results suggest that the ecDNA oncogenic makeup determines unique evolutionary trajectories. New concepts such as ecDNA clonality and heteroplasmy require a refined evolutionary interpretation of genomic data in a large subset of GBMs.</p><p><strong>Significance: </strong>We study spatial patterns of ecDNA-amplified oncogenes and their evolutionary properties in human GBM, revealing an ecDNA landscape and ecDNA oncogene-specific evolutionary histories. ecDNA accumulation can precede clonal expansion, facilitating the emergence of EGFR oncogenic variants, reframing our interpretation of genomic data in a large subset of GBMs. See related commentary by Korsah et al., p. 1979.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2078-2095"},"PeriodicalIF":33.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12498097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145013770","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":"Correction: Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers.","authors":"Jingjing Jiang, Lingyan Jiang, Benjamin J Maldonato, Yingyun Wang, Matthew Holderfield, Ida Aronchik, Ian P Winters, Zeena Salman, Cristina Blaj, Marie Menard, Jens Brodbeck, Zhe Chen, Xing Wei, Michael J Rosen, Yevgeniy Gindin, Bianca J Lee, James W Evans, Stephanie Chang, Zhican Wang, Kyle J Seamon, Dylan Parsons, James Cregg, Abby Marquez, Aidan C A Tomlinson, Jason K Yano, John E Knox, Elsa Quintana, Andrew J Aguirre, Kathryn C Arbour, Abby Reed, W Clay Gustafson, Adrian L Gill, Elena S Koltun, David Wildes, Jacqueline A M Smith, Zhengping Wang, Mallika Singh","doi":"10.1158/2159-8290.CD-25-1519","DOIUrl":"10.1158/2159-8290.CD-25-1519","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 10","pages":"2186"},"PeriodicalIF":33.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12498095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231520","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":"From Discovery to Diagnosis: A Perspective for Circulating Tumor Cells in Personalized Oncology.","authors":"Catherine Alix-Panabières, Klaus Pantel","doi":"10.1158/2159-8290.CD-25-0164","DOIUrl":"10.1158/2159-8290.CD-25-0164","url":null,"abstract":"<p><p>Circulating tumor cells (CTCs) are cells shed from tumors into the bloodstream, providing a unique source of information on tumor biology. CTCs can be collected through liquid biopsy, offering a noninvasive option to track cancer progression and treatment responses. Whereas ctDNA gives valuable insights into genomic alterations, CTCs allow for the direct analysis of cellular protein and RNA expression, essential for identifying targetable markers and resistance mechanisms. Resistance to cancer therapies is often due to genetic and phenotypic adaptations within tumor cells. CTC analysis can help track these adaptations, providing real-time insights into evolving resistance mechanisms and suggesting alternative therapies.</p><p><strong>Significance: </strong>Enumeration and molecular characterization of CTCs provide unique insights into the biology of cancer metastasis as well as clinically relevant information on tumor evolution, risk assessment, and therapy response in individual patients with solid malignancies.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1985-2001"},"PeriodicalIF":33.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871610","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":"Boosting Sensitivity through a Multianalyte Cerebrospinal Fluid Approach for Diagnosis, Prognostication, and Immune Monitoring for Brain Tumors","authors":"Hannah K. Weiss, Camila S. Fang, Daniel A. Orringer, Alexandra M. Miller","doi":"10.1158/2159-8290.cd-25-1162","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1162","url":null,"abstract":"Summary: The CSF-BAM assay, developed by Pearlman, Wang, and colleagues, integrates the detection of somatic mutations, genome aneuploidy, and B- and T-cell receptor clonality from a single cerebrospinal fluid DNA library to increase the sensitivity of cerebrospinal fluid to diagnosis and track brain tumors. See related article by Pearlman et al., p. 2002","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"86 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228972","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":"Epigenetic and transcriptional programs define osteosarcoma subtypes and establish targetable vulnerabilities.","authors":"Eunice Lopez-Fuentes,Andrew S Clugston,Alex G Lee,Leanne C Sayles,Natalie Sorensen,María V Pons Ventura,Stanley G Leung,Truc Dinh,Marcus R Breese,E Alejandro Sweet-Cordero","doi":"10.1158/2159-8290.cd-25-0237","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0237","url":null,"abstract":"Osteosarcoma is a genomically complex tumor characterized by widespread structural rearrangements. This complexity has limited development of therapeutic strategies informed by molecular mechanisms of oncogenesis. We hypothesized that epigenetic mechanisms could drive distinct subtypes of osteosarcoma. Through analysis of chromatin accessibility, we identified an \"early osteoblast-derived\" (EOD) cell state characterized by upregulation of transcription factors associated with early bone development, and a \"late osteoblast-derived\" state (LOD), characterized by upregulation of genes involved in late bone development. We then defined core regulatory circuitries governing the underlying gene expression programs in these two cell states. Multiomic single-cell analysis indicates that these cell states co-exist in a single tumor. Finally, using a panel of patient-derived xenograft models, we identified differential drug responses dependent on these cellular states. These findings create opportunities for developing new combination therapy strategies for osteosarcoma treatment and underscore the value of defining epigenetic subtypes in highly genomically complex cancers.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"76 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209071","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}