Cancer discoveryPub Date : 2025-03-05DOI: 10.1158/2159-8290.CD-25-0282
Rebecca L Eccles, Gabriela Carreno, Lorenzo de la Rica, Gemma M Balmer, David Scott
{"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":"https://doi.org/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":"OF1-OF5"},"PeriodicalIF":29.7,"publicationDate":"2025-03-05","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}
Cancer discoveryPub Date : 2025-03-03DOI: 10.1158/2159-8290.CD-24-0827
Mei Luo, Jingwen Yang, Alejandro A Schäffer, Chengxuan Chen, Yuan Liu, Yamei Chen, Chunru Lin, Lixia Diao, Yong Zang, Yanyan Lou, Huda Salman, Gordon B Mills, Eytan Ruppin, Leng Han
{"title":"Ancestral Differences in Anticancer Treatment Efficacy and Their Underlying Genomic and Molecular Alterations.","authors":"Mei Luo, Jingwen Yang, Alejandro A Schäffer, Chengxuan Chen, Yuan Liu, Yamei Chen, Chunru Lin, Lixia Diao, Yong Zang, Yanyan Lou, Huda Salman, Gordon B Mills, Eytan Ruppin, Leng Han","doi":"10.1158/2159-8290.CD-24-0827","DOIUrl":"10.1158/2159-8290.CD-24-0827","url":null,"abstract":"<p><strong>Significance: </strong>Our study charts a global landscape of ancestry-associated differences in therapeutic efficacy, highlighting the importance of considering ancestry in anticancer therapies.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"511-529"},"PeriodicalIF":29.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726233","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}
Cancer discoveryPub Date : 2025-03-03DOI: 10.1158/2159-8290.CD-24-1885
Zhiwei Zhou, Kenneth D Westover
{"title":"Beyond First-Generation KRAS Inhibitors: BBO-8520 Tests the Dual Mechanism Hypothesis.","authors":"Zhiwei Zhou, Kenneth D Westover","doi":"10.1158/2159-8290.CD-24-1885","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1885","url":null,"abstract":"<p><p>This issue highlights the development of a first-in-class small-molecule covalent KRASG12C inhibitor, BBO-8520, which targets both the active (ON) and inactive (OFF) states of KRAS. This dual-state targeting offers a significant opportunity to overcome the resistance mechanisms that have limited the efficacy of first-generation KRAS inhibitors and addresses critical challenges in KRAS-targeted therapy. See related article by Maciag et al., p. 578.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 3","pages":"455-457"},"PeriodicalIF":29.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536598","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}
Cancer discoveryPub Date : 2025-03-03DOI: 10.1158/2159-8290.CD-25-0054
Armin Wiegering, Friedrich W Uthe, Thomas Jamieson, Yvonne Ruoss, Melanie Hüttenrauch, Maritta Küspert, Christina Pfann, Colin Nixon, Steffi Herold, Susanne Walz, Lyudmyla Taranets, Christoph-Thomas Germer, Andreas Rosenwald, Owen J Sansom, Martin Eilers
{"title":"Correction: Targeting Translation Initiation Bypasses Signaling Crosstalk Mechanisms That Maintain High MYC Levels in Colorectal Cancer.","authors":"Armin Wiegering, Friedrich W Uthe, Thomas Jamieson, Yvonne Ruoss, Melanie Hüttenrauch, Maritta Küspert, Christina Pfann, Colin Nixon, Steffi Herold, Susanne Walz, Lyudmyla Taranets, Christoph-Thomas Germer, Andreas Rosenwald, Owen J Sansom, Martin Eilers","doi":"10.1158/2159-8290.CD-25-0054","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-25-0054","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 3","pages":"656"},"PeriodicalIF":29.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536616","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}
Cancer discoveryPub Date : 2025-03-03DOI: 10.1158/2159-8290.cd-24-1326
Sarah C. Moser, Jos Jonkers
{"title":"Thirty Years of BRCA1: Mechanistic Insights and Their Impact on Mutation Carriers","authors":"Sarah C. Moser, Jos Jonkers","doi":"10.1158/2159-8290.cd-24-1326","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1326","url":null,"abstract":"Thirty years ago, the cloning of the first breast cancer susceptibility gene, BRCA1, marked a milestone in our understanding of hereditary breast and ovarian cancers. This discovery initiated extensive research into DNA repair mechanisms, BRCA1-associated tumorigenesis, and therapeutic interventions. Despite these advances, critical questions remain unanswered, such as the evolution of BRCA1-associated tumors and their tissue specificity. These issues hinder the development of effective treatment and prevention strategies, which ultimately aim to improve the quality of life for BRCA1 mutation carriers. In this review, we discuss current knowledge, identify existing gaps, and suggest possible avenues to tackle these challenges. Significance: Here, we explore the impact of three decades of BRCA1 research on the lives of mutation carriers and propose strategies to improve the prevention and treatment of BRCA1-associated cancer.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"84 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532802","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}
Cancer discoveryPub Date : 2025-03-03DOI: 10.1158/2159-8290.CD-24-1883
Jiani Zhu, Ekaterina K Koltsova
{"title":"Two Faces of NOTCH1 in Liver Cancer and Immunotherapy.","authors":"Jiani Zhu, Ekaterina K Koltsova","doi":"10.1158/2159-8290.CD-24-1883","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1883","url":null,"abstract":"<p><p>High NOTCH1 expression inversely correlates with hepatocellular carcinoma tumorigenicity and contributes to better immune checkpoint inhibitor responses in male patients, whereas high NOTCH1 in females coincides with heightened hepatocellular carcinoma incidence and poor immunotherapy responses. Activated NOTCH1 generates enhanced antitumor CD8+ T-cell responses in a sex chromosome-dependent manner and facilitates responsiveness to immunotherapy treatment in males, whereas it drives immune escape in females. See related article by Lindblad et al., p. 495.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 3","pages":"452-454"},"PeriodicalIF":29.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536662","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}
Cancer discoveryPub Date : 2025-03-03DOI: 10.1158/2159-8290.CD-24-1884
Shensi Shen, Zhen Tan
{"title":"Illuminating a Dark Kinase in the Mesenchymal Cancer Cell State.","authors":"Shensi Shen, Zhen Tan","doi":"10.1158/2159-8290.CD-24-1884","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1884","url":null,"abstract":"<p><p>Killarney and colleagues identify PKN2 as a critical driver of mesenchymal cancer cell survival and drug resistance through YAP/TAZ activation. Targeting PKN2 in combination with first-line targeted therapies offers a potential strategy to eliminate mesenchymal-like drug-tolerant persister cells. See related article by Killarney et al., p. 595.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 3","pages":"458-460"},"PeriodicalIF":29.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536658","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}
Cancer discoveryPub Date : 2025-03-03DOI: 10.1158/2159-8290.CD-25-0208
Sriram Venneti, Abed Rahman Kawakibi, Sunjong Ji, Sebastian M Waszak, Stefan R Sweha, Mateus Mota, Matthew Pun, Akash Deogharkar, Chan Chung, Rohinton S Tarapore, Samuel Ramage, Andrew Chi, Patrick Y Wen, Isabel Arrillaga-Romany, Tracy T Batchelor, Nicholas A Butowski, Ashley Sumrall, Nicole Shonka, Rebecca A Harrison, John de Groot, Minesh Mehta, Matthew D Hall, Doured Daghistani, Timothy F Cloughesy, Benjamin M Ellingson, Kevin Beccaria, Pascale Varlet, Michelle M Kim, Yoshie Umemura, Hugh Garton, Andrea Franson, Jonathan Schwartz, Rajan Jain, Maureen Kachman, Heidi Baum, Charles F Burant, Sophie L Mottl, Rodrigo T Cartaxo, Vishal John, Dana Messinger, Tingting Qin, Erik Peterson, Peter Sajjakulnukit, Karthik Ravi, Alyssa Waugh, Dustin Walling, Yujie Ding, Ziyun Xia, Anna Schwendeman, Debra Hawes, Fusheng Yang, Alexander R Judkins, Daniel Wahl, Costas A Lyssiotis, Daniel de la Nava, Marta M Alonso, Augustine Eze, Jasper Spitzer, Susanne V Schmidt, Ryan J Duchatel, Matthew D Dun, Jason E Cain, Li Jiang, Sylwia A Stopka, Gerard Baquer, Michael S Regan, Mariella G Filbin, Nathalie Y R Agar, Lili Zhao, Chandan Kumar-Sinha, Rajen Mody, Arul Chinnaiyan, Ryo Kurokawa, Drew Pratt, Viveka N Yadav, Jacques Grill, Cassie Kline, Sabine Mueller, Adam Resnick, Javad Nazarian, Joshua E Allen, Yazmin Odia, Sharon L Gardner, Carl Koschmann
{"title":"Correction: Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways.","authors":"Sriram Venneti, Abed Rahman Kawakibi, Sunjong Ji, Sebastian M Waszak, Stefan R Sweha, Mateus Mota, Matthew Pun, Akash Deogharkar, Chan Chung, Rohinton S Tarapore, Samuel Ramage, Andrew Chi, Patrick Y Wen, Isabel Arrillaga-Romany, Tracy T Batchelor, Nicholas A Butowski, Ashley Sumrall, Nicole Shonka, Rebecca A Harrison, John de Groot, Minesh Mehta, Matthew D Hall, Doured Daghistani, Timothy F Cloughesy, Benjamin M Ellingson, Kevin Beccaria, Pascale Varlet, Michelle M Kim, Yoshie Umemura, Hugh Garton, Andrea Franson, Jonathan Schwartz, Rajan Jain, Maureen Kachman, Heidi Baum, Charles F Burant, Sophie L Mottl, Rodrigo T Cartaxo, Vishal John, Dana Messinger, Tingting Qin, Erik Peterson, Peter Sajjakulnukit, Karthik Ravi, Alyssa Waugh, Dustin Walling, Yujie Ding, Ziyun Xia, Anna Schwendeman, Debra Hawes, Fusheng Yang, Alexander R Judkins, Daniel Wahl, Costas A Lyssiotis, Daniel de la Nava, Marta M Alonso, Augustine Eze, Jasper Spitzer, Susanne V Schmidt, Ryan J Duchatel, Matthew D Dun, Jason E Cain, Li Jiang, Sylwia A Stopka, Gerard Baquer, Michael S Regan, Mariella G Filbin, Nathalie Y R Agar, Lili Zhao, Chandan Kumar-Sinha, Rajen Mody, Arul Chinnaiyan, Ryo Kurokawa, Drew Pratt, Viveka N Yadav, Jacques Grill, Cassie Kline, Sabine Mueller, Adam Resnick, Javad Nazarian, Joshua E Allen, Yazmin Odia, Sharon L Gardner, Carl Koschmann","doi":"10.1158/2159-8290.CD-25-0208","DOIUrl":"10.1158/2159-8290.CD-25-0208","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 3","pages":"657"},"PeriodicalIF":29.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11873718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536611","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}
Cancer discoveryPub Date : 2025-03-03DOI: 10.1158/2159-8290.CD-24-1215
Katherine E Lindblad, Romain Donne, Ian Liebling, Marina Barcena-Varela, Anthony Lozano, Marina Ruiz de Galarreta, Maxime Dhainaut, Nesteene J Param, Bruno Giotti, Sarah Cappuyns, Takahiro Kodama, Yulei Wang, Alice O Kamphorst, Alexander M Tsankov, Amaia Lujambio
{"title":"NOTCH1 Drives Sexually Dimorphic Immune Responses in Hepatocellular Carcinoma.","authors":"Katherine E Lindblad, Romain Donne, Ian Liebling, Marina Barcena-Varela, Anthony Lozano, Marina Ruiz de Galarreta, Maxime Dhainaut, Nesteene J Param, Bruno Giotti, Sarah Cappuyns, Takahiro Kodama, Yulei Wang, Alice O Kamphorst, Alexander M Tsankov, Amaia Lujambio","doi":"10.1158/2159-8290.CD-24-1215","DOIUrl":"10.1158/2159-8290.CD-24-1215","url":null,"abstract":"<p><p>Hepatocellular carcinoma presents strong sexual dimorphism, being two to three times more frequent in males than in females; however, the role of sex in response to immunotherapies in HCC remains unknown. We demonstrate that NOTCH1, an understudied oncogene in HCC, elicits sexually dimorphic antitumor immunity and response to FDA-approved immunotherapies. Surprisingly, males harboring NOTCH1-driven tumors displayed enhanced antitumor immune responses, which, in mice, were mediated by dendritic and T cells. Conversely, females harboring NOTCH1-driven tumors presented immune evasion and resistance to immunotherapies through a defect in dendritic cell (DC)-mediated priming and activation of CD8+ T cells in mice, which was restored therapeutically with CD40 agonism. Mechanistically, the sexually dimorphic immunity was mediated by genes in the sex chromosomes but not by sex hormones. Together, our study unravels an unexpected association between NOTCH1 and sex in cancer immunity and highlights the potential of restoring the DC-CD8+ T-cell axis with CD40 agonism to improve outcomes. Significance: Although HCC presents strong sexual dimorphism, the role of sex in response to immunotherapies remains elusive. With a novel HCC mouse model and validation in patients with HCC, we demonstrate that NOTCH1 disrupts antitumor immunity specifically in females through a mechanism mediated by sex chromosome genes, which is reversed with CD40 agonism. See related commentary by Zhu and Koltsova, p. 452.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"495-510"},"PeriodicalIF":29.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666978","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}
Cancer discoveryPub Date : 2025-03-03DOI: 10.1158/2159-8290.CD-24-0928
Shane T Killarney, Gabriel Mesa, Rachel Washart, Benjamin Mayro, Kerry Dillon, Suzanne E Wardell, Madeline Newlin, Min Lu, Areej Abu Rmaileh, Nicky Liu, Donald P McDonnell, Ann Marie Pendergast, Kris C Wood
{"title":"PKN2 Is a Dependency of the Mesenchymal-like Cancer Cell State.","authors":"Shane T Killarney, Gabriel Mesa, Rachel Washart, Benjamin Mayro, Kerry Dillon, Suzanne E Wardell, Madeline Newlin, Min Lu, Areej Abu Rmaileh, Nicky Liu, Donald P McDonnell, Ann Marie Pendergast, Kris C Wood","doi":"10.1158/2159-8290.CD-24-0928","DOIUrl":"10.1158/2159-8290.CD-24-0928","url":null,"abstract":"<p><p>Cancer cells exploit a mesenchymal-like transcriptional state (MLS) to survive drug treatments. Although the MLS is well characterized, few therapeutic vulnerabilities targeting this program have been identified. In this study, we systematically identify the dependency network of mesenchymal-like cancers through an analysis of gene essentiality scores in ∼800 cancer cell lines, nominating a poorly studied kinase, PKN2, as a top therapeutic target of the MLS. Coessentiality relationships, biochemical experiments, and genomic analyses of patient tumors revealed that PKN2 promotes mesenchymal-like cancer growth through a PKN2-SAV1-TAZ signaling mechanism. Notably, pairing genetic PKN2 inhibition with clinically relevant targeted therapies against EGFR, KRAS, and BRAF suppresses drug resistance by depleting mesenchymal-like drug-tolerant persister cells. These findings provide evidence that PKN2 is a core regulator of the Hippo tumor suppressor pathway and highlight the potential of PKN2 inhibition as a generalizable therapeutic strategy to overcome drug resistance driven by the MLS across cancer contexts. Significance: This work identifies PKN2 as a core member of the Hippo signaling pathway, and its inhibition blocks YAP/TAZ-driven tumorigenesis. Furthermore, this study discovers PKN2-TAZ as arguably the most selective dependency of mesenchymal-like cancers and supports specific inhibition of PKN2 as a provocative strategy to overcome drug resistance in diverse cancer contexts. See related commentary by Shen and Tan, p. 458.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"595-615"},"PeriodicalIF":29.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666981","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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