Pub Date : 2026-01-09DOI: 10.1158/2159-8290.cd-rw2026-003
{"title":"Genetic Context Shapes Selection or Decay of Driver Mutations in Colon Cancer.","authors":"","doi":"10.1158/2159-8290.cd-rw2026-003","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-rw2026-003","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"255 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949630","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 : 2026-01-08DOI: 10.1158/2159-8290.cd-25-1761
Ferran Fece de la Cruz, Andreas Varkaris, Parasvi S. Patel, Elijah W. Kushner, Alvin A. Morales-Giron, Sangmi Sandra. Lee, Ankit Singh, Clara T. Kim, Bryanna L. Norden, Sara Ehnstrom, Jakob M. Riedl, Jacquelyn M. Curtis, Haley Barnes, Allison M. Kehlmann, Nicholas J. Chevalier, Hitomi S. Okuma, Manisha Patel, Lori J. Wirth, Brendan Connell, Francis Nugent, Leontios Pappas, Kayao Lau, Dejan Juric, Jessica L. Hopkins, Keelan Z. Guiley, Kevan M. Shokat, Doga C. Gulhan, Aparna R. Parikh, Ryan B. Corcoran
The tumor suppressor TP53 is the most frequently altered gene in cancer, and the Y220C hotspot, found in 1.8% of TP53-mutant tumors, creates a druggable cavity that destabilizes p53. Rezatapopt, a first-in-class, orally bioavailable reactivator of Y220C-mutant p53, has demonstrated promising initial efficacy in the phase 1/2 PYNNACLE trial. We report the first clinical mechanisms of resistance to this therapeutic class. Profiling of circulating tumor DNA, tumor biopsies, and rapid autopsy specimens upon rezatapopt progression revealed multiple heterogenous secondary TP53 alterations in cis with Y220C, including: (1) DNA-binding domain mutations or frameshift/nonsense mutations that abolish transcriptional activity, and (2) mutations within the Y220C binding surface predicted to hinder drug binding. Functional modeling confirmed these double mutants eliminate p53 reactivation and target gene induction by rezatapopt. These findings establish a molecular framework for resistance to p53 Y220C reactivators and inform strategies to overcome resistance with next-generation agents.
{"title":"Acquired on-target alterations drive clinical resistance to p53-Y220C reactivators","authors":"Ferran Fece de la Cruz, Andreas Varkaris, Parasvi S. Patel, Elijah W. Kushner, Alvin A. Morales-Giron, Sangmi Sandra. Lee, Ankit Singh, Clara T. Kim, Bryanna L. Norden, Sara Ehnstrom, Jakob M. Riedl, Jacquelyn M. Curtis, Haley Barnes, Allison M. Kehlmann, Nicholas J. Chevalier, Hitomi S. Okuma, Manisha Patel, Lori J. Wirth, Brendan Connell, Francis Nugent, Leontios Pappas, Kayao Lau, Dejan Juric, Jessica L. Hopkins, Keelan Z. Guiley, Kevan M. Shokat, Doga C. Gulhan, Aparna R. Parikh, Ryan B. Corcoran","doi":"10.1158/2159-8290.cd-25-1761","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1761","url":null,"abstract":"The tumor suppressor TP53 is the most frequently altered gene in cancer, and the Y220C hotspot, found in 1.8% of TP53-mutant tumors, creates a druggable cavity that destabilizes p53. Rezatapopt, a first-in-class, orally bioavailable reactivator of Y220C-mutant p53, has demonstrated promising initial efficacy in the phase 1/2 PYNNACLE trial. We report the first clinical mechanisms of resistance to this therapeutic class. Profiling of circulating tumor DNA, tumor biopsies, and rapid autopsy specimens upon rezatapopt progression revealed multiple heterogenous secondary TP53 alterations in cis with Y220C, including: (1) DNA-binding domain mutations or frameshift/nonsense mutations that abolish transcriptional activity, and (2) mutations within the Y220C binding surface predicted to hinder drug binding. Functional modeling confirmed these double mutants eliminate p53 reactivation and target gene induction by rezatapopt. These findings establish a molecular framework for resistance to p53 Y220C reactivators and inform strategies to overcome resistance with next-generation agents.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"392 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920234","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 : 2026-01-07DOI: 10.1158/2159-8290.cd-rw2026-001
{"title":"Bacterial Elements Detected in Brain Tumors May Shape Tumor Microenvironment.","authors":"","doi":"10.1158/2159-8290.cd-rw2026-001","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-rw2026-001","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"265 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949632","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 : 2026-01-05DOI: 10.1158/2159-8290.cd-25-1085
Michael Lee,Yuannyu Zhang,Jun Yi Stanley Lim,Tao Dai,James Ye,Margaret B Cervantes,Varun Sondhi,Sisi Zheng,Yoon Jung Kim,Brandon Chen,Ralph J DeBerardinis,Jian Xu
Retrotransposons are genomic parasites frequently reactivated in cancers, where their mobility can cause genetic alterations. However, it remains unclear whether their gene products contribute to cancer beyond mutagenesis. Here, we uncover a chromatin-associated function of RNAs from Long Interspersed Element-1 (LINE-1), the only autonomous retrotransposon in the human genome. Subcellular-resolved transcriptomics revealed that LINE-1 RNAs are primarily nascent transcripts produced by full-length, cell-type-specific genomic copies of evolutionarily young subfamilies. Using a long-read chromosome conformation assay, we identified a class of highly interactive LINE-1 loci required for gene expression across cancer subtypes, revealing an unexpected regulatory role for LINE-1 locus transcription in oncogenic gene control. LINE-1 RNA depletion disrupted LINE-1-centric chromatin interactions and downregulated associated genes, whereas genomic insertion of an inducible LINE-1 generated de novo chromatin interactions in a transcription-dependent manner. Therefore, beyond their mutagenic potential, retrotransposons also regulate cancer gene expression by nucleating chromatin architecture through their transcriptional activity.
{"title":"LINE-1 Locus Transcription Nucleates Oncogenic Chromatin Architecture.","authors":"Michael Lee,Yuannyu Zhang,Jun Yi Stanley Lim,Tao Dai,James Ye,Margaret B Cervantes,Varun Sondhi,Sisi Zheng,Yoon Jung Kim,Brandon Chen,Ralph J DeBerardinis,Jian Xu","doi":"10.1158/2159-8290.cd-25-1085","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1085","url":null,"abstract":"Retrotransposons are genomic parasites frequently reactivated in cancers, where their mobility can cause genetic alterations. However, it remains unclear whether their gene products contribute to cancer beyond mutagenesis. Here, we uncover a chromatin-associated function of RNAs from Long Interspersed Element-1 (LINE-1), the only autonomous retrotransposon in the human genome. Subcellular-resolved transcriptomics revealed that LINE-1 RNAs are primarily nascent transcripts produced by full-length, cell-type-specific genomic copies of evolutionarily young subfamilies. Using a long-read chromosome conformation assay, we identified a class of highly interactive LINE-1 loci required for gene expression across cancer subtypes, revealing an unexpected regulatory role for LINE-1 locus transcription in oncogenic gene control. LINE-1 RNA depletion disrupted LINE-1-centric chromatin interactions and downregulated associated genes, whereas genomic insertion of an inducible LINE-1 generated de novo chromatin interactions in a transcription-dependent manner. Therefore, beyond their mutagenic potential, retrotransposons also regulate cancer gene expression by nucleating chromatin architecture through their transcriptional activity.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"4 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897445","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 : 2025-12-31DOI: 10.1158/2159-8290.cd-nw2025-0118
Patients with relapsed or refractory follicular lymphoma have few treatment options-with a rituximab-lenalidomide (R2) pairing considered the only alternative to immunochemotherapy. But data from the pivotal phase III EPCORE LF-1 trial show that a three-drug combination of epcoritimab plus R2 can reduce the risk of disease progression and death by 79% compared with R2 alone.
{"title":"Epcoritimab Combo Could Be New Standard for Some FLs.","authors":"","doi":"10.1158/2159-8290.cd-nw2025-0118","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2025-0118","url":null,"abstract":"Patients with relapsed or refractory follicular lymphoma have few treatment options-with a rituximab-lenalidomide (R2) pairing considered the only alternative to immunochemotherapy. But data from the pivotal phase III EPCORE LF-1 trial show that a three-drug combination of epcoritimab plus R2 can reduce the risk of disease progression and death by 79% compared with R2 alone.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"4 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897448","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 : 2025-12-31DOI: 10.1158/2159-8290.CD-24-0853
Dennis J Yuan, John Zinno, Theo Botella, Dalia Dhingra, Shu Wang, Allegra G Hawkins, Ariel Swett, Jesus Sotelo, Ramya Raviram, Clayton Hughes, Catherine Potenski, Katharine D Godfrey, Kara M Ainsworth, Shuzhen Xu, Jianwen Que, Julian A Abrams, Akira Yokoyama, Nobuyuki Kakiuchi, Seishi Ogawa, Dan A Landau
Somatic mosaicism is pervasively observed in human aging, with clonal expansions of cells harboring mutations in recurrently mutated driver genes. Bulk sequencing of tissues captures mutation frequencies, but cannot reconstruct clonal architectures nor delineate how driver mutations impact cellular phenotypes. We developed single-cell Genotype-to-Phenotype sequencing (scG2P) for high-throughput, highly-multiplexed, joint capture of genotyping of mutation hotspots and mRNA markers. We applied scG2P to aged esophagus samples from six individuals and observed large numbers of clones with a single driver event, accompanied by rare clones with two driver mutations. NOTCH1 mutants dominate the clonal landscape and are linked to stunted epithelial differentiation, while TP53 mutants promote clonal expansion through both differentiation biases and increased cell cycling. Thus, joint single-cell highly multiplexed capture of somatic mutations and mRNA transcripts enables high resolution reconstruction of clonal architecture and associated phenotypes in solid tissue somatic mosaicism.
{"title":"Genotype-to-phenotype mapping of somatic clonal mosaicism via single-cell co-capture of DNA mutations and mRNA transcripts.","authors":"Dennis J Yuan, John Zinno, Theo Botella, Dalia Dhingra, Shu Wang, Allegra G Hawkins, Ariel Swett, Jesus Sotelo, Ramya Raviram, Clayton Hughes, Catherine Potenski, Katharine D Godfrey, Kara M Ainsworth, Shuzhen Xu, Jianwen Que, Julian A Abrams, Akira Yokoyama, Nobuyuki Kakiuchi, Seishi Ogawa, Dan A Landau","doi":"10.1158/2159-8290.CD-24-0853","DOIUrl":"10.1158/2159-8290.CD-24-0853","url":null,"abstract":"<p><p>Somatic mosaicism is pervasively observed in human aging, with clonal expansions of cells harboring mutations in recurrently mutated driver genes. Bulk sequencing of tissues captures mutation frequencies, but cannot reconstruct clonal architectures nor delineate how driver mutations impact cellular phenotypes. We developed single-cell Genotype-to-Phenotype sequencing (scG2P) for high-throughput, highly-multiplexed, joint capture of genotyping of mutation hotspots and mRNA markers. We applied scG2P to aged esophagus samples from six individuals and observed large numbers of clones with a single driver event, accompanied by rare clones with two driver mutations. NOTCH1 mutants dominate the clonal landscape and are linked to stunted epithelial differentiation, while TP53 mutants promote clonal expansion through both differentiation biases and increased cell cycling. Thus, joint single-cell highly multiplexed capture of somatic mutations and mRNA transcripts enables high resolution reconstruction of clonal architecture and associated phenotypes in solid tissue somatic mosaicism.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":33.3,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12874418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892093","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}
Pub Date : 2025-12-31DOI: 10.1158/2159-8290.cd-nw2025-0117
Twenty-five years ago, the FDA gave the first approval to an antibody-drug conjugate (ADC), the CD33-targeting gemtuzumab ozogamicin for acute myeloid leukemia. As the drug faced setbacks and redemption-it was withdrawn in 2010 following poor phase III trial results but reapproved in 2017 at a lower dose-a surge of pharmaceutical interest in ADCs has yielded newly approved agents and new strategies for developing them.
{"title":"Cancer Throughlines: 25 Years after First Approval, ADCs Continue to Pick up Steam.","authors":"","doi":"10.1158/2159-8290.cd-nw2025-0117","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2025-0117","url":null,"abstract":"Twenty-five years ago, the FDA gave the first approval to an antibody-drug conjugate (ADC), the CD33-targeting gemtuzumab ozogamicin for acute myeloid leukemia. As the drug faced setbacks and redemption-it was withdrawn in 2010 following poor phase III trial results but reapproved in 2017 at a lower dose-a surge of pharmaceutical interest in ADCs has yielded newly approved agents and new strategies for developing them.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"8 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897444","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 : 2025-12-22DOI: 10.1158/2159-8290.cd-nw2025-0115
Three trials report positive data for the noncovalent Bruton tyrosine kinase inhibitor pirtobrutinib and a potential successor, rocbrutinib, in chronic lymphocytic leukemia. One study of previously untreated patients found a 24-month progression-free survival of 93.4% for pirtobrutinib, versus 70.7% for bendamustine and rituximab. The second study suggests the drug is noninferior to the covalent inhibitor ibrutinib in previously untreated or relapsed or refractory patients. The third study found an overall response rate of 62.5% for rocbrutinib in previously treated patients.
{"title":"New BTK Inhibitors May Combat Resistance in CLL","authors":"","doi":"10.1158/2159-8290.cd-nw2025-0115","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2025-0115","url":null,"abstract":"Three trials report positive data for the noncovalent Bruton tyrosine kinase inhibitor pirtobrutinib and a potential successor, rocbrutinib, in chronic lymphocytic leukemia. One study of previously untreated patients found a 24-month progression-free survival of 93.4% for pirtobrutinib, versus 70.7% for bendamustine and rituximab. The second study suggests the drug is noninferior to the covalent inhibitor ibrutinib in previously untreated or relapsed or refractory patients. The third study found an overall response rate of 62.5% for rocbrutinib in previously treated patients.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"30 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801200","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 : 2025-12-22DOI: 10.1158/2159-8290.cd-nw2025-0114
By pairing a BCMA-targeted T-cell engager with an anti-CD38 antibody, researchers achieved strikingly deep remissions and sharply reduced relapse risk in patients with relapsed myeloma. The results suggest this dual immune-directed strategy could challenge current treatment sequencing, including when to deploy engineered T-cell therapies.
{"title":"Two Drugs, One Stunning Myeloma Result","authors":"","doi":"10.1158/2159-8290.cd-nw2025-0114","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2025-0114","url":null,"abstract":"By pairing a BCMA-targeted T-cell engager with an anti-CD38 antibody, researchers achieved strikingly deep remissions and sharply reduced relapse risk in patients with relapsed myeloma. The results suggest this dual immune-directed strategy could challenge current treatment sequencing, including when to deploy engineered T-cell therapies.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"24 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801082","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 : 2025-12-19DOI: 10.1158/2159-8290.cd-25-0974
Yiyi Ji, Cheng-Wei Ju, Lei Chen, Kai Shen, Ruopeng Su, Ang Li, Xinyu Liu, Bo Liu, Xinran Zhang, Ruitu Lyu, Peng Xia, Han Li, Yiqian Pan, Yunzheng Liu, Man Hin Tse, Yizheng Xue, Hongyang Qian, Na Jing, Helen He. Zhu, Liangliang Wang, Li-Sheng Zhang, Shu-Heng Jiang, Weiwei Zhang, Liang Dong, Zejun Yan, Jiahua Pan, Yinjie Zhu, Jiangbo Wei, Qi Wang, Wei Xue
Neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant subtype of prostate cancer characterized by lineage plasticity. While metabolic and signaling molecules are increasingly recognized as modulators of tumor progression, their role in cell fate transition remains unclear. NE tumors produce and accumulate serotonin, a neurotransmitter that regulates diverse physiological processes. Here, we identify a tumor-intrinsic serotonin axis as key driver of NEPC lineage commitment and progression. NEPC endogenously synthesize serotonin via aromatic L-amino acid decarboxylase (DDC) and reuptake through the transporter SLC6A4. Mechanistically, high level of intracellular serotonin promotes histone serotonylation at H3K4me3Q5, reconfiguring the H3K4me3 chromatin landscape and downstream gene expression, which drives induced NE differentiation and is associated with suppressed androgen receptor signaling. Pharmacological inhibition of 5-HT synthesis using the FDA-approved DDC inhibitor carbidopa significantly impairs tumor growth and prolongs survival in both genetically engineered and patient-derived xenograft models, highlighting histone serotonylation as a druggable vulnerability in NEPC.
{"title":"Serotonin modulates lineage plasticity in neuroendocrine prostate cancer via epigenetic reprogramming","authors":"Yiyi Ji, Cheng-Wei Ju, Lei Chen, Kai Shen, Ruopeng Su, Ang Li, Xinyu Liu, Bo Liu, Xinran Zhang, Ruitu Lyu, Peng Xia, Han Li, Yiqian Pan, Yunzheng Liu, Man Hin Tse, Yizheng Xue, Hongyang Qian, Na Jing, Helen He. Zhu, Liangliang Wang, Li-Sheng Zhang, Shu-Heng Jiang, Weiwei Zhang, Liang Dong, Zejun Yan, Jiahua Pan, Yinjie Zhu, Jiangbo Wei, Qi Wang, Wei Xue","doi":"10.1158/2159-8290.cd-25-0974","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0974","url":null,"abstract":"Neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant subtype of prostate cancer characterized by lineage plasticity. While metabolic and signaling molecules are increasingly recognized as modulators of tumor progression, their role in cell fate transition remains unclear. NE tumors produce and accumulate serotonin, a neurotransmitter that regulates diverse physiological processes. Here, we identify a tumor-intrinsic serotonin axis as key driver of NEPC lineage commitment and progression. NEPC endogenously synthesize serotonin via aromatic L-amino acid decarboxylase (DDC) and reuptake through the transporter SLC6A4. Mechanistically, high level of intracellular serotonin promotes histone serotonylation at H3K4me3Q5, reconfiguring the H3K4me3 chromatin landscape and downstream gene expression, which drives induced NE differentiation and is associated with suppressed androgen receptor signaling. Pharmacological inhibition of 5-HT synthesis using the FDA-approved DDC inhibitor carbidopa significantly impairs tumor growth and prolongs survival in both genetically engineered and patient-derived xenograft models, highlighting histone serotonylation as a druggable vulnerability in NEPC.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"93 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777585","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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