Pub Date : 2025-11-03DOI: 10.1158/2159-8290.cd-25-1431
Vidhi Chandra, Le Li, Florencia McAllister
Summary: Morder, Nguyen, Wilfahrt, and colleagues report that nonnutritive sweeteners impair the efficacy of anti–PD-1 therapy through mechanisms that involve regulation of microbiota and metabolites. Their findings underscore the clinical relevance of long-term lifestyle interventions, such as limiting daily intake of nonnutritive sweeteners, across multiple cancer types. See related article by Morder et al., p. 2278
{"title":"The Bitter Aftertaste of Artificial Sweeteners in Cancer Immunotherapy","authors":"Vidhi Chandra, Le Li, Florencia McAllister","doi":"10.1158/2159-8290.cd-25-1431","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1431","url":null,"abstract":"Summary: Morder, Nguyen, Wilfahrt, and colleagues report that nonnutritive sweeteners impair the efficacy of anti–PD-1 therapy through mechanisms that involve regulation of microbiota and metabolites. Their findings underscore the clinical relevance of long-term lifestyle interventions, such as limiting daily intake of nonnutritive sweeteners, across multiple cancer types. See related article by Morder et al., p. 2278","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"152 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427417","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}
Pub Date : 2025-10-30DOI: 10.1158/2159-8290.cd-25-0581
Wei Zhao, Tongwu Zhang, Xing Hua, Phuc H. Hoang, Mona Miraftab, Monjoy Saha, John P. McElderry, Jian Sang, Olivia W. Lee, Caleb Hartman, Azhar Khandekar, Sunandini Sharma, Frank J. Colón-Matos, Samuel Anyaso-Samuel, Difei Wang, Kristine Jones, Amy Hutchinson, Belynda Hicks, Jennifer Rosenbaum, Xiaoming Zhong, Yang Yang, Angela C. Pesatori, Dario Consonni, David C. Christiani, Kin Chung Leung, Maria Pik. Wong, Marta Manczuk, Jolanta Lissowska, Beata Świątkowska, Anush Mukeria, Oxana Shangina, David Zaridze, Ivana Holcatova, Dana Mates, Sasa Milosavljevic, Simona Ognjanovic, Milan Savic, Milica Kontic, Valerie Gaborieau, Paul Brennan, Oscar Arrieta, Yohan Bossé, Eric S. Edell, Matthew B. Schabath, Paul Hofman, Luis Mas, Sai S. Yendamuri, Chih-Yi Chen, I-Shou Chang, Chao Agnes. Hsiung, Geoffrey Liu, Jacobo Martinez Santamaría, Bonnie E. Gould Rothberg, Karun Mutreja, Scott Lawrence, Nathaniel Rothman, Ludmil B. Alexandrov, Charles Leduc, Marina K. Baine, Philippe Joubert, Lynette M. Sholl, William D. Travis, Robert Homer, Qing Lan, Stephen J. Chanock, Lixing Yang, Soo-Ryum Yang, Jianxin Shi, Maria Teresa Landi
Understanding tumor cell dynamics can improve prognosis and treatment but remains limited for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA-seq data from 684 NS-LUAD and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histological data further characterized the subtypes. 'Steady', marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver genes’ alterations, is linked to prolonged survival and low immune evasion. 'Proliferative' shows high proliferation markers, TP53 mutations, and gene fusions. 'Chaotic', with high epithelial-to-mesenchymal transition markers, has the worst prognosis even within stage I tumors. Lacking known molecular or histological characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the classification and predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving early-stage NS-LUAD prognostication in clinical settings.
{"title":"A prognostic signature for lung adenocarcinoma in patients who have never smoked","authors":"Wei Zhao, Tongwu Zhang, Xing Hua, Phuc H. Hoang, Mona Miraftab, Monjoy Saha, John P. McElderry, Jian Sang, Olivia W. Lee, Caleb Hartman, Azhar Khandekar, Sunandini Sharma, Frank J. Colón-Matos, Samuel Anyaso-Samuel, Difei Wang, Kristine Jones, Amy Hutchinson, Belynda Hicks, Jennifer Rosenbaum, Xiaoming Zhong, Yang Yang, Angela C. Pesatori, Dario Consonni, David C. Christiani, Kin Chung Leung, Maria Pik. Wong, Marta Manczuk, Jolanta Lissowska, Beata Świątkowska, Anush Mukeria, Oxana Shangina, David Zaridze, Ivana Holcatova, Dana Mates, Sasa Milosavljevic, Simona Ognjanovic, Milan Savic, Milica Kontic, Valerie Gaborieau, Paul Brennan, Oscar Arrieta, Yohan Bossé, Eric S. Edell, Matthew B. Schabath, Paul Hofman, Luis Mas, Sai S. Yendamuri, Chih-Yi Chen, I-Shou Chang, Chao Agnes. Hsiung, Geoffrey Liu, Jacobo Martinez Santamaría, Bonnie E. Gould Rothberg, Karun Mutreja, Scott Lawrence, Nathaniel Rothman, Ludmil B. Alexandrov, Charles Leduc, Marina K. Baine, Philippe Joubert, Lynette M. Sholl, William D. Travis, Robert Homer, Qing Lan, Stephen J. Chanock, Lixing Yang, Soo-Ryum Yang, Jianxin Shi, Maria Teresa Landi","doi":"10.1158/2159-8290.cd-25-0581","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0581","url":null,"abstract":"Understanding tumor cell dynamics can improve prognosis and treatment but remains limited for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA-seq data from 684 NS-LUAD and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histological data further characterized the subtypes. 'Steady', marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver genes’ alterations, is linked to prolonged survival and low immune evasion. 'Proliferative' shows high proliferation markers, TP53 mutations, and gene fusions. 'Chaotic', with high epithelial-to-mesenchymal transition markers, has the worst prognosis even within stage I tumors. Lacking known molecular or histological characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the classification and predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving early-stage NS-LUAD prognostication in clinical settings.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"120 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145397458","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}
Pub Date : 2025-10-27DOI: 10.1158/2159-8290.cd-25-1212
Lin Zhou,Kelly D DeMarco,Katherine C Murphy,Zhenpeng Wu,Jinping Li,Calvin Johnson,Bin Liu,Hadiya K Giwa,Boyang Ma,Nikita Bhalerao,Junhui Li,Zhong Jiang,Shi Bai,Chaitanya N Parikh,Tianyi Ye,Karl Simin,Lihua J Zhu,Jason R Pitarresi,Hong Wu,Marcus Ruscetti
Cellular senescence is a well-established tumor-suppressive cell cycle arrest program. However, chronic inflammation through the senescence-associated secretory phenotype (SASP) can alternatively drive immune suppression and cancer progression. Using prostate cancer patient samples and murine models, we find p16+ and p21+ senescent cells accumulate throughout malignant progression and associate with immune suppression. Single cell sequencing revealed p16 and p21 mark distinct epithelial and stromal senescent populations, with p21+ non-tumor cells expressing the highest SASP. p21+ stromal cell removal blocked the SASP to reverse immune suppression and slow tumor growth. Senolytic BCL-xL inhibitor treatment could clear p21+ stromal senescent cells, reactivating anti-tumor CD8+ T cell immunity and inhibiting prostate tumor progression in mice. Suppression of BCL-xL or p21 also potentiated anti-PD-1 ICB in preclinical prostate cancer models. Our findings demonstrate that targeting p21+ senescent stromal populations can yield therapeutic benefits in advanced prostate cancer through activating anti-tumor immunity and enhancing immunotherapy outcomes.
{"title":"P21-positive senescent stromal cells promote prostate cancer immune suppression and progression that can be reversed by senolytic therapy.","authors":"Lin Zhou,Kelly D DeMarco,Katherine C Murphy,Zhenpeng Wu,Jinping Li,Calvin Johnson,Bin Liu,Hadiya K Giwa,Boyang Ma,Nikita Bhalerao,Junhui Li,Zhong Jiang,Shi Bai,Chaitanya N Parikh,Tianyi Ye,Karl Simin,Lihua J Zhu,Jason R Pitarresi,Hong Wu,Marcus Ruscetti","doi":"10.1158/2159-8290.cd-25-1212","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1212","url":null,"abstract":"Cellular senescence is a well-established tumor-suppressive cell cycle arrest program. However, chronic inflammation through the senescence-associated secretory phenotype (SASP) can alternatively drive immune suppression and cancer progression. Using prostate cancer patient samples and murine models, we find p16+ and p21+ senescent cells accumulate throughout malignant progression and associate with immune suppression. Single cell sequencing revealed p16 and p21 mark distinct epithelial and stromal senescent populations, with p21+ non-tumor cells expressing the highest SASP. p21+ stromal cell removal blocked the SASP to reverse immune suppression and slow tumor growth. Senolytic BCL-xL inhibitor treatment could clear p21+ stromal senescent cells, reactivating anti-tumor CD8+ T cell immunity and inhibiting prostate tumor progression in mice. Suppression of BCL-xL or p21 also potentiated anti-PD-1 ICB in preclinical prostate cancer models. Our findings demonstrate that targeting p21+ senescent stromal populations can yield therapeutic benefits in advanced prostate cancer through activating anti-tumor immunity and enhancing immunotherapy outcomes.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"48 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357803","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}
Inhibitors of the oncogene KRAS hold promise for treating metastatic CRC (mCRC). Here we show that a selective, covalent small molecule inhibitor of the active (ON) conformation of RAS-G12D, RMC-9945, exerts durable disease control in preclinical CRC models of early liver metastasis, but its therapeutic activity was diminished in the advanced metastatic disease. RMC-9945-treated metastases underwent a transition from a poor-prognosis-associated Emp1⁺ transcriptional state to a WNT-driven Lgr5⁺ stem cell-like state that withstands the absence of RAS-G12D activity. This cell state change occurred within hours of RAS(ON) inhibitor treatment through a shift in transcription factor usage that involved limited chromatin remodeling. Forced conversion of metastatic cells to the Lgr5⁺ state through RAS-G12D inhibition, followed by genetic ablation of this population, reduced metastatic burden and prolonged survival in a mouse mCRC model. Overall, these preclinical findings demonstrate a central role for oncogenic KRAS in governing cellular plasticity in mCRC.
{"title":"A plastic EMP1⁺ to LGR5⁺ cell state conversion as a bypass to KRAS-G12D pharmacological inhibition in metastatic colorectal cancer.","authors":"Alessia Centonze,Adrià-Jaume Roura,Meritxell Novillo-Font,Cristina Giordano,Xavier Hernando-Momblona,Montserrat Llanses,Paula Prats,Marta Sevillano,Débora Cabot,Mireia Novell,Gabriel Pabst,Florian Andersch,Adrià Cañellas-Socias,Chong Zhang,Nikolaos-Nikiforos Giakoumakis,Hugh Sparks,Chris Dunsby,Julien Colombelli,Asunción Fernández-Barral,Elena Sancho,Camille Stephan-Otto Attolini,Alberto Muñoz,Antonio Barbachano,Héctor G Palmer,Jordi Martínez-Quintanilla,Johannes Zuber,Cristina Blaj,Elsa Quintana,Carme Cortina,Marc A Marti-Renom,Eduard Batlle","doi":"10.1158/2159-8290.cd-25-0679","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0679","url":null,"abstract":"Inhibitors of the oncogene KRAS hold promise for treating metastatic CRC (mCRC). Here we show that a selective, covalent small molecule inhibitor of the active (ON) conformation of RAS-G12D, RMC-9945, exerts durable disease control in preclinical CRC models of early liver metastasis, but its therapeutic activity was diminished in the advanced metastatic disease. RMC-9945-treated metastases underwent a transition from a poor-prognosis-associated Emp1⁺ transcriptional state to a WNT-driven Lgr5⁺ stem cell-like state that withstands the absence of RAS-G12D activity. This cell state change occurred within hours of RAS(ON) inhibitor treatment through a shift in transcription factor usage that involved limited chromatin remodeling. Forced conversion of metastatic cells to the Lgr5⁺ state through RAS-G12D inhibition, followed by genetic ablation of this population, reduced metastatic burden and prolonged survival in a mouse mCRC model. Overall, these preclinical findings demonstrate a central role for oncogenic KRAS in governing cellular plasticity in mCRC.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"1 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339263","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}
Pub Date : 2025-10-21DOI: 10.1158/2159-8290.cd-25-0525
Mengxiong Wang,Kathryn T Bieging-Rolett,Alyssa M Kaiser,Colleen A Brady,John H Lockhart,Sofia Ferreira,Kha T Nguyen,Arati Rajeevan,Simone A Evans,Tianyu Zhao,Nitin Raj,Arielle Elkrief,Sam E Tischfield,Marc Ladanyi,Michael G Ozawa,Nam Q Bui,Christopher T Chen,Elsa R Flores,Laura D Attardi
Pharmacological restoration of p53 tumor suppressor function is a conceptually appealing therapeutic strategy for the many deadly cancers with compromised p53 activity, including lung adenocarcinoma (LUAD). However, the p53 pathway has remained undruggable, partly because of insufficient understanding of how to drive effective therapeutic responses without toxicity. Here, we use mouse and human models to deconstruct the transcriptional programs and sequelae underlying robust therapeutic responses in LUAD. We show that p53 drives potent tumor regression by direct Tsc2 transactivation, leading to mTORC1 inhibition and TFEB nuclear accumulation, which in turn triggers lysosomal gene expression programs, autophagy, and cellular senescence. Senescent LUAD cells secrete factors to recruit macrophages, precipitating cancer cell phagocytosis and tumor regression. Collectively, our analyses reveal a surprisingly complex cascade of events underlying a p53 therapeutic response in LUAD and illuminate targetable nodes for p53 combination therapies, thus establishing a critical framework for optimizing p53-based therapeutics.
{"title":"p53 drives lung cancer regression through a TSC2/TFEB-dependent senescence program.","authors":"Mengxiong Wang,Kathryn T Bieging-Rolett,Alyssa M Kaiser,Colleen A Brady,John H Lockhart,Sofia Ferreira,Kha T Nguyen,Arati Rajeevan,Simone A Evans,Tianyu Zhao,Nitin Raj,Arielle Elkrief,Sam E Tischfield,Marc Ladanyi,Michael G Ozawa,Nam Q Bui,Christopher T Chen,Elsa R Flores,Laura D Attardi","doi":"10.1158/2159-8290.cd-25-0525","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0525","url":null,"abstract":"Pharmacological restoration of p53 tumor suppressor function is a conceptually appealing therapeutic strategy for the many deadly cancers with compromised p53 activity, including lung adenocarcinoma (LUAD). However, the p53 pathway has remained undruggable, partly because of insufficient understanding of how to drive effective therapeutic responses without toxicity. Here, we use mouse and human models to deconstruct the transcriptional programs and sequelae underlying robust therapeutic responses in LUAD. We show that p53 drives potent tumor regression by direct Tsc2 transactivation, leading to mTORC1 inhibition and TFEB nuclear accumulation, which in turn triggers lysosomal gene expression programs, autophagy, and cellular senescence. Senescent LUAD cells secrete factors to recruit macrophages, precipitating cancer cell phagocytosis and tumor regression. Collectively, our analyses reveal a surprisingly complex cascade of events underlying a p53 therapeutic response in LUAD and illuminate targetable nodes for p53 combination therapies, thus establishing a critical framework for optimizing p53-based therapeutics.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"39 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331636","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}
Pub Date : 2025-10-17DOI: 10.1158/2159-8290.cd-25-1457
Vivek Subbiah
Tumor-agnostic therapies represent a revolutionary shift from century-old anatomic classifications to molecular-driven cancer treatment, in which therapeutic decisions are based on what drives the tumor rather than where it arises. This perspective calls for a transformative acceleration of tissue-agnostic drug development from today's 10 approvals to 50 to 100 within 25 years to eliminate therapeutic inequities and ensure every patient receives the right therapy based on their tumor's molecular identity, not anatomic accident.
{"title":"Rethinking Cancer Drug Development through Tumor-Agnostic Precision Medicine.","authors":"Vivek Subbiah","doi":"10.1158/2159-8290.cd-25-1457","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1457","url":null,"abstract":"Tumor-agnostic therapies represent a revolutionary shift from century-old anatomic classifications to molecular-driven cancer treatment, in which therapeutic decisions are based on what drives the tumor rather than where it arises. This perspective calls for a transformative acceleration of tissue-agnostic drug development from today's 10 approvals to 50 to 100 within 25 years to eliminate therapeutic inequities and ensure every patient receives the right therapy based on their tumor's molecular identity, not anatomic accident.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"64 1","pages":"OF1-OF7"},"PeriodicalIF":28.2,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305451","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}
Pub Date : 2025-10-15DOI: 10.1158/2159-8290.cd-25-0587
Cheng Huang,Yan Gao,Jianfeng Chen,Jing Han Hong,Yue Jiang,Kelila Xin Ye Chai,Yingxi Li,Peili Wang,Yali Wang,Jiuping Gao,Xian Zeng,Rong Xiao,Haixia He,Peiyong Guan,Jason Yongsheng Chan,Jing Quan Lim,Anand D Jeyasekharan,Huang Dachuan,Jin-Xin Bei,Bin Tean Teh,Soon Thye Lim,Qiang Yu,Choon Kiat Ong,Huiqiang Huang,Jing Tan
Anti-PD-1 immunotherapy has demonstrated significant antitumor efficacy in relapsed or refractory NK/T-cell lymphoma (R/R NKTL), but resistance remains a substantial challenge. In this study, we evaluate DNA methyltransferase (DNMT) inhibitors combined with anti-PD-1 mAb in 21 patients with R/R NKTL for whom prior immunotherapy failed. This combination therapy achieved an objective response rate of 66.7% (14/21), with a complete response rate of 47.6% (10/21) and a 2-year overall survival rate of 50.2%. Preclinical models revealed that anti-PD-1 resistance was linked to the absence of CD8+ T-cell infiltration and suppressed IFN pathways. DNMT inhibitors reversed these effects, restoring CD8+ T-cell activities and tumor sensitivity to PD-1 blockade. Mechanistically, DNMT inhibitors triggered DNA demethylation of endogenous retroviral elements, activating viral mimicry via upregulated endogenous nucleic acids and type I IFN signaling. These findings underscore DNMT inhibitors' role in overcoming PD-1 resistance and support their combination with anti-PD-1 as a promising strategy for R/R NKTL.SIGNIFICANCEResistance to anti-PD-1 immunotherapy remains a substantial challenge in R/R NKTL. In this study, we reported that combining DNMT inhibitors with anti-PD-1 mAb achieves a high complete response rate of 47.6% in immunotherapy-R/R NKTL patients. Mechanistically, DNMT inhibitors potentiate anti-PD-1 efficacy by triggering viral mimicry, remodeling the immune microenvironment and augmenting antitumor immunity.
{"title":"Priming with DNMT Inhibitors Potentiates PD-1 Immunotherapy by Triggering Viral Mimicry in Relapsed/Refractory NK/T-cell Lymphoma.","authors":"Cheng Huang,Yan Gao,Jianfeng Chen,Jing Han Hong,Yue Jiang,Kelila Xin Ye Chai,Yingxi Li,Peili Wang,Yali Wang,Jiuping Gao,Xian Zeng,Rong Xiao,Haixia He,Peiyong Guan,Jason Yongsheng Chan,Jing Quan Lim,Anand D Jeyasekharan,Huang Dachuan,Jin-Xin Bei,Bin Tean Teh,Soon Thye Lim,Qiang Yu,Choon Kiat Ong,Huiqiang Huang,Jing Tan","doi":"10.1158/2159-8290.cd-25-0587","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0587","url":null,"abstract":"Anti-PD-1 immunotherapy has demonstrated significant antitumor efficacy in relapsed or refractory NK/T-cell lymphoma (R/R NKTL), but resistance remains a substantial challenge. In this study, we evaluate DNA methyltransferase (DNMT) inhibitors combined with anti-PD-1 mAb in 21 patients with R/R NKTL for whom prior immunotherapy failed. This combination therapy achieved an objective response rate of 66.7% (14/21), with a complete response rate of 47.6% (10/21) and a 2-year overall survival rate of 50.2%. Preclinical models revealed that anti-PD-1 resistance was linked to the absence of CD8+ T-cell infiltration and suppressed IFN pathways. DNMT inhibitors reversed these effects, restoring CD8+ T-cell activities and tumor sensitivity to PD-1 blockade. Mechanistically, DNMT inhibitors triggered DNA demethylation of endogenous retroviral elements, activating viral mimicry via upregulated endogenous nucleic acids and type I IFN signaling. These findings underscore DNMT inhibitors' role in overcoming PD-1 resistance and support their combination with anti-PD-1 as a promising strategy for R/R NKTL.SIGNIFICANCEResistance to anti-PD-1 immunotherapy remains a substantial challenge in R/R NKTL. In this study, we reported that combining DNMT inhibitors with anti-PD-1 mAb achieves a high complete response rate of 47.6% in immunotherapy-R/R NKTL patients. Mechanistically, DNMT inhibitors potentiate anti-PD-1 efficacy by triggering viral mimicry, remodeling the immune microenvironment and augmenting antitumor immunity.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"8 1","pages":"OF1-OF18"},"PeriodicalIF":28.2,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288500","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}
Pub Date : 2025-10-15DOI: 10.1158/2159-8290.cd-25-0605
Franziska Siegel,Stephan Siegel,Kristýna Kotýnková,Gizem Karsli Uzunbas,Daniel Korr,Haruna Tomono,Sawyer Andersen,Daniel Denney,Markus Berger,Volker K Schulze,Timothy A Lewis,Bethany Kaplan,Sven Golfier,Jérémie Mortier,Roman C Hillig,Ulf Boemer,Kirstin Petersen,Knut Eis,Sybil Williams,Dominik Rüttinger,Andrew D Cherniack,Herbert H Loong,Koichi Goto,Paolo Grassi,Matthew Meyerson,Heidi Greulich
Exon 20 insertions of HER2, encoded by ERBB2, and other activating HER2 mutations occur in 2-4% of lung adenocarcinomas, but there are only limited therapeutic options available for these patients. Sevabertinib (BAY 2927088) is a potent and reversible dual EGFR-HER2 inhibitor that is selective with respect to wild-type EGFR. Here, we report the preclinical activity of sevabertinib in lung cancer models harboring alterations of HER2, including exon 20 insertions, point mutations, and amplification of wild-type ERBB2. We furthermore demonstrate the activity of sevabertinib in a cancer cell line dependent on a fusion of NRG1, a ligand for the HER2 family member and heterodimerization partner, HER3. Finally, we report patient responses to sevabertinib from a Phase 1/2 clinical trial, indicating potential benefit for patients with HER2-mutant lung cancer.
{"title":"Sevabertinib, a Reversible HER2 Inhibitor with Activity in Lung Cancer.","authors":"Franziska Siegel,Stephan Siegel,Kristýna Kotýnková,Gizem Karsli Uzunbas,Daniel Korr,Haruna Tomono,Sawyer Andersen,Daniel Denney,Markus Berger,Volker K Schulze,Timothy A Lewis,Bethany Kaplan,Sven Golfier,Jérémie Mortier,Roman C Hillig,Ulf Boemer,Kirstin Petersen,Knut Eis,Sybil Williams,Dominik Rüttinger,Andrew D Cherniack,Herbert H Loong,Koichi Goto,Paolo Grassi,Matthew Meyerson,Heidi Greulich","doi":"10.1158/2159-8290.cd-25-0605","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0605","url":null,"abstract":"Exon 20 insertions of HER2, encoded by ERBB2, and other activating HER2 mutations occur in 2-4% of lung adenocarcinomas, but there are only limited therapeutic options available for these patients. Sevabertinib (BAY 2927088) is a potent and reversible dual EGFR-HER2 inhibitor that is selective with respect to wild-type EGFR. Here, we report the preclinical activity of sevabertinib in lung cancer models harboring alterations of HER2, including exon 20 insertions, point mutations, and amplification of wild-type ERBB2. We furthermore demonstrate the activity of sevabertinib in a cancer cell line dependent on a fusion of NRG1, a ligand for the HER2 family member and heterodimerization partner, HER3. Finally, we report patient responses to sevabertinib from a Phase 1/2 clinical trial, indicating potential benefit for patients with HER2-mutant lung cancer.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"91 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288321","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}
Pub Date : 2025-10-14DOI: 10.1158/2159-8290.cd-24-1224
Charles H. Earnshaw, Poppy Dunn, Shih-Chieh Chiang, Agrin Moeini, Maria A. Koufaki, Eduardo Bonavita, Massimo Russo, Laetitia Nebot-Bral, Kimberley Hockenhull, Erin Richardson, Anna Pidoux, Charlotte R. Bell, Alexander R. Baker, Richard Reeves, Robert Sellers, Sudhakar Sahoo, Victoria Fife, Matthew G. Roberts, Theophile Bigirumurame, Caroline Dive, Julia Newton-Bishop, Jérémie Nsengimana, Christopher E.M. Griffiths, Santiago Zelenay
Half of patients with advanced melanoma fail to benefit from immune checkpoint blockade, and novel treatments are urgently required. Testing topical medications for anticancer activity in an immunotherapy-resistant murine melanoma model, we found that, counterintuitively, glucocorticoids (GCs) elicit rapid cytotoxic T lymphocyte (CTL)-dependent tumor control. Genetic ablation of the GC receptor in different cellular compartments revealed that GCs acted not on immune cells but directly on tumor cells to downregulate the expression of glycoprotein A repetitions predominant (GARP). This inhibited TGF β signaling and unleashed CTL killing. In agreement, GCs stimulated tumor control in multiple cancer models but only if the tumors also responded to pharmacologic inhibition of TGF β signaling. Furthermore, patients with melanoma with high GC receptor expression or signaling showed improved prognosis and lower TGF β signaling in tumor-infiltrating CTLs. Additionally, elevated GARP expression correlated with reduced survival, including in immunotherapy-treated patients. Thus, the GARP/TGF β axis emerges as a GC-sensitive cancer cell–intrinsic immune-evasive mechanism. Significance: This study uncovers a surprising role for GCs in triggering CD8+ T cell–dependent tumor control through downregulation of GARP and thus TGF β signaling. Analysis of samples from patients with melanoma suggested that GARP expression may serve as both a biomarker of poor antitumor immunity and a therapeutic target to improve the response to immunotherapy.
{"title":"Glucocorticoids Unleash Immune-dependent Melanoma Control through Inhibition of the GARP/TGF β Axis","authors":"Charles H. Earnshaw, Poppy Dunn, Shih-Chieh Chiang, Agrin Moeini, Maria A. Koufaki, Eduardo Bonavita, Massimo Russo, Laetitia Nebot-Bral, Kimberley Hockenhull, Erin Richardson, Anna Pidoux, Charlotte R. Bell, Alexander R. Baker, Richard Reeves, Robert Sellers, Sudhakar Sahoo, Victoria Fife, Matthew G. Roberts, Theophile Bigirumurame, Caroline Dive, Julia Newton-Bishop, Jérémie Nsengimana, Christopher E.M. Griffiths, Santiago Zelenay","doi":"10.1158/2159-8290.cd-24-1224","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1224","url":null,"abstract":"Half of patients with advanced melanoma fail to benefit from immune checkpoint blockade, and novel treatments are urgently required. Testing topical medications for anticancer activity in an immunotherapy-resistant murine melanoma model, we found that, counterintuitively, glucocorticoids (GCs) elicit rapid cytotoxic T lymphocyte (CTL)-dependent tumor control. Genetic ablation of the GC receptor in different cellular compartments revealed that GCs acted not on immune cells but directly on tumor cells to downregulate the expression of glycoprotein A repetitions predominant (GARP). This inhibited TGF β signaling and unleashed CTL killing. In agreement, GCs stimulated tumor control in multiple cancer models but only if the tumors also responded to pharmacologic inhibition of TGF β signaling. Furthermore, patients with melanoma with high GC receptor expression or signaling showed improved prognosis and lower TGF β signaling in tumor-infiltrating CTLs. Additionally, elevated GARP expression correlated with reduced survival, including in immunotherapy-treated patients. Thus, the GARP/TGF β axis emerges as a GC-sensitive cancer cell–intrinsic immune-evasive mechanism. Significance: This study uncovers a surprising role for GCs in triggering CD8+ T cell–dependent tumor control through downregulation of GARP and thus TGF β signaling. Analysis of samples from patients with melanoma suggested that GARP expression may serve as both a biomarker of poor antitumor immunity and a therapeutic target to improve the response to immunotherapy.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"86 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145289190","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}
Pub Date : 2025-10-09DOI: 10.1158/2159-8290.cd-24-0414
Daniel D. Azorín, Dirk C. Hoffmann, Nils R. Hebach, Erik Jung, David Hausmann, Miriam Ratliff, Ling Hai, Sandra Horschitz, Ammar Jabali, Matthias Osswald, Matthia A. Karreman, Tobias Kessler, Susann Wendler, Chanté D. Mayer, Cathrin Löb, Pascal Lehnert, Gina Cebulla, Denise Reibold, Rajiv K. Khajuria, Pino Bordignon, Andreas E. Moor, Tim Holland-Letz, Jill Reckless, Nigel Ramsden, David Grainger, Anna Kreshuk, Philipp Koch, Wolfgang Wick, Sophie Heuer, Frank Winkler
Glioblastomas are incurable primary brain tumors that depend on neural-like cellular processes, tumor microtubes (TMs), to invade the brain. TMs also interconnect single tumor cells to a communicating multicellular network that resists current therapies. Here, we developed a combined, comprehensive in vitro/in vivo anti-TM drug screening approach, including machine-learning-based analysis tools. Two Protein Kinase C (PKC) modulators robustly inhibited TM formation and pacemaker tumor cell-driven, TM-mediated glioblastoma cell network communication. Since TM-unconnected tumor cells exhibited increased sensitivity to cytotoxic therapy, the PKC activator TPPB was combined with radiotherapy, and long-term intravital 2-photon microscopy paired with spatially resolved multiomics revealed anti-TM and anti-tumor effects. TPPB treatment also decreased the expression of tweety family member 1 (TTYH1), a key driver of invasive TMs. Our study establishes a novel screening pipeline for anti-TM drug development, identifies a TM master regulator pathway, and supports the approach of TM targeting for efficient brain tumor therapies.
{"title":"Screening for Tumor Microtube-Targeting Drugs Identifies PKC Modulators as Multipotent Inhibitors of Glioblastoma Progression","authors":"Daniel D. Azorín, Dirk C. Hoffmann, Nils R. Hebach, Erik Jung, David Hausmann, Miriam Ratliff, Ling Hai, Sandra Horschitz, Ammar Jabali, Matthias Osswald, Matthia A. Karreman, Tobias Kessler, Susann Wendler, Chanté D. Mayer, Cathrin Löb, Pascal Lehnert, Gina Cebulla, Denise Reibold, Rajiv K. Khajuria, Pino Bordignon, Andreas E. Moor, Tim Holland-Letz, Jill Reckless, Nigel Ramsden, David Grainger, Anna Kreshuk, Philipp Koch, Wolfgang Wick, Sophie Heuer, Frank Winkler","doi":"10.1158/2159-8290.cd-24-0414","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0414","url":null,"abstract":"Glioblastomas are incurable primary brain tumors that depend on neural-like cellular processes, tumor microtubes (TMs), to invade the brain. TMs also interconnect single tumor cells to a communicating multicellular network that resists current therapies. Here, we developed a combined, comprehensive in vitro/in vivo anti-TM drug screening approach, including machine-learning-based analysis tools. Two Protein Kinase C (PKC) modulators robustly inhibited TM formation and pacemaker tumor cell-driven, TM-mediated glioblastoma cell network communication. Since TM-unconnected tumor cells exhibited increased sensitivity to cytotoxic therapy, the PKC activator TPPB was combined with radiotherapy, and long-term intravital 2-photon microscopy paired with spatially resolved multiomics revealed anti-TM and anti-tumor effects. TPPB treatment also decreased the expression of tweety family member 1 (TTYH1), a key driver of invasive TMs. Our study establishes a novel screening pipeline for anti-TM drug development, identifies a TM master regulator pathway, and supports the approach of TM targeting for efficient brain tumor therapies.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"26 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246868","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}
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