Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-pr004
Andrew Seeber, William E. Arter, Seema Qamar, Cinzia Sgambato, Amal Alex, Kadi Saar, Julia Doh, Martin Kulander, Tuomas Knowles, Shilpi Arora
Fusion oncogenes drive malignant transformation by altering transcriptional programs, disrupting cellular homeostasis, and frequently rewiring protein condensate networks. Emerging evidence suggests that aberrant condensate formation is a key mechanism through which these fusion proteins exert oncogenic control. Specifically, by amplifying transcriptional output, sequestering cofactors, and enforcing pathological gene expression states. Despite their genetic validation as oncogenic drivers, many fusion proteins remain pharmacologically intractable due to the absence of catalytic domains or well-defined binding pockets. To overcome this, we developed an integrated discovery platform that directly assesses the biophysical and functional properties of fusion protein-driven condensates and enables identification of small molecules that disrupt these oncogenic assemblies. Using protein language models and in silico predictors of phase separation, we systematically mapped condensate-forming potential across recurrent oncogenic fusions catalogued in TCGA. This analysis revealed that most fusion proteins (including EML4-ALK and EWS-FLI1) harbor extensive intrinsically disordered regions (IDRs) that promote abnormal condensation and transcriptional dysregulation. We further identified disease-specific variants that alter condensate formation relative to wild-type proteins, providing mechanistic insight into oncogenic gain- and loss-of-function events. To experimentally validate and therapeutically exploit these findings, we established PhaseScan™, a high-throughput droplet microfluidics screening platform capable of quantitatively profiling condensate dynamics and screening thousands of compounds against reconstituted fusion condensates to identify therapeutically relevant small molecule inhibitors. Across multiple fusion proteins, PhaseScan™ identified small molecules that selectively disrupt aberrant condensates while sparing physiological assemblies such as nuclear speckles and stress granules. Using EML4-ALK as a representative model, we demonstrated that compound-mediated condensate dissolution disrupts oncogenic ALK signaling and reverses oncogenic phenotypes in cell-based systems. Our results highlight condensate biology as a generalizable vulnerability across fusion-driven cancers and demonstrate the feasibility of discovering small molecules against fusion proteins traditionally considered undruggable. By integrating AI-driven predictive modeling, and on-target molecular high-throughput screening, our platform provides a roadmap for rationally identifying and drugging fusion protein condensates. This approach establishes condensate-targeted therapeutics as a novel class of precision medicines for patients with fusion-positive malignancies. Citation Format: Andrew Seeber, William E. Arter, Seema Qamar, Cinzia Sgambato, Amal Alex, Kadi Saar, Julia Doh, Martin Kulander, Tuomas Knowles, Shilpi Arora. Targeting aberrant condensate formation in fusion-
融合癌基因通过改变转录程序、破坏细胞稳态和频繁地重新连接蛋白凝聚网络来驱动恶性转化。新出现的证据表明，异常凝聚形成是这些融合蛋白发挥致癌控制作用的关键机制。具体来说，通过放大转录输出，隔离辅因子，并加强病理基因表达状态。尽管它们的基因验证是致癌驱动因素，但由于缺乏催化结构域或明确的结合口袋，许多融合蛋白在药理学上仍然难以处理。为了克服这一点，我们开发了一个集成的发现平台，直接评估融合蛋白驱动凝聚物的生物物理和功能特性，并能够识别破坏这些致癌组装的小分子。利用蛋白质语言模型和相分离的计算机预测因子，我们系统地绘制了TCGA中分类的复发性致癌融合的凝聚形成电位。该分析显示，大多数融合蛋白（包括EML4-ALK和EWS-FLI1）含有广泛的内在失调区（IDRs），可促进异常凝聚和转录失调。我们进一步确定了疾病特异性变异，这些变异改变了相对于野生型蛋白的凝聚物形成，为致癌功能的获得和丧失事件提供了机制上的见解。为了实验验证和治疗利用这些发现，我们建立了PhaseScan™，这是一种高通量液滴微流体筛选平台，能够定量分析冷凝物动力学，并筛选数千种针对重组融合冷凝物的化合物，以确定治疗相关的小分子抑制剂。在多种融合蛋白中，PhaseScan™识别出选择性破坏异常凝聚体的小分子，同时保留核斑点和应力颗粒等生理组装。使用EML4-ALK作为代表性模型，我们证明了化合物介导的冷凝物溶解破坏了基于细胞的系统中的致癌ALK信号传导并逆转了致癌表型。我们的研究结果强调了凝聚生物学在融合驱动的癌症中是一种普遍的脆弱性，并证明了发现小分子对抗传统上被认为不可药物的融合蛋白的可行性。通过整合ai驱动的预测建模和靶向分子高通量筛选，我们的平台为融合蛋白凝聚物的合理鉴定和给药提供了路线图。这种方法建立凝血靶向治疗作为一类新的精准药物的融合阳性恶性肿瘤患者。引文格式：Andrew Seeber， William E. Arter, Seema Qamar, Cinzia Sgambato, Amal Alex, Kadi Saar, Julia Doh, Martin Kulander, Tuomas Knowles, Shilpi Arora。基于集成发现平台的融合阳性肿瘤异常凝析物形成靶向研究[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): nr PR004。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-a024
James E. Corban, Max Frenkel, Srivatsan Raman
Oncofusions, cancer-causing chimeric proteins formed by chromosomal rearrangements, are key drivers in approximately 16% of all cancer cases. These fusion proteins are associated with a wide range of malignancies, including varieties of leukemia, lung cancer, and sarcoma. Thousands of unique oncofusions have been identified in recent years, yet most of these fusion proteins lack mechanistic annotation. Many oncofusions dysregulate chromatin architecture in complex ways that are not yet fully elucidated. Investigating these chromatin alterations is both labor-intensive and costly, limiting the feasibility of large-scale studies. This lack of mechanistic insight has hindered the development of targeted therapies, with only a handful of efficacious small-molecule inhibitors directed toward oncofusions currently in clinical trials or approved for patient use. To address this critical gap, we adapted our recently developed PROD-ATAC method into a high-throughput, scalable platform to systematically elucidate the effects of dozens of candidate inhibitory small molecules on the chromatin dysregulation profiles induced by a pooled library of diverse oncofusions. In the PROD-ATAC scheme, a pooled protein-coding variant library is expressed in a single disease-agnostic cell line, and scATAC-seq (single-cell assay for transposase accessible chromatin) catalogs each variant’s effect on the chromatin landscape. We applied PROD-ATAC to simultaneously assay the chromatin regulatory impact of >40 small molecule inhibitors against a panel of tens of oncofusions (including the majority of patient-identified fusion sequences causal for Ewing sarcoma) in a single assay, generating genome-wide chromatin accessibility datasets representative of >1,000 unique drug - fusion interactions. In this manner, we characterized several small molecules as previously unidentified inhibitors of multiple oncofusions. Certain inhibitors were found to abrogate the chromatin dysregulation caused by an oncofusion either globally or in a targeted cell signaling pathway-specific manner. By profiling multiple rare fusions causal for the same cancers, we identified separate instances of homogenous and heterogenous modes of chromatin dysregulation associated with distinct fusion proteins. In this work, PROD-ATAC chromatin accessibility readouts coupled the identification of novel oncofusion inhibitors with the characterization of each inhibitor’s impact on the epigenetic landscape of oncofusion-expressing cells. Citation Format: James E. Corban, Max Frenkel, Srivatsan Raman. High-throughput characterization of inhibitor impacts on chromatin dysregulation induced by oncofusions [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr A024.
肿瘤混淆，即由染色体重排形成的致癌嵌合蛋白，是约16%癌症病例的关键驱动因素。这些融合蛋白与多种恶性肿瘤有关，包括各种白血病、肺癌和肉瘤。近年来已经发现了数千种独特的混淆，但大多数这些融合蛋白缺乏机制注释。许多混乱以尚未完全阐明的复杂方式失调染色质结构。研究这些染色质改变既费力又昂贵，限制了大规模研究的可行性。这种机制的缺乏阻碍了靶向治疗的发展，目前只有少数有效的小分子抑制剂用于临床试验或批准患者使用。为了解决这一关键空白，我们将我们最近开发的PROD-ATAC方法改编为高通量，可扩展的平台，系统地阐明了数十种候选抑制小分子对不同混淆库诱导的染色质失调谱的影响。在PROD-ATAC方案中，一个汇集的蛋白质编码变异体文库在单个疾病不确定细胞系中表达，scATAC-seq（转座酶可及染色质单细胞测定）编目了每个变异体对染色质的影响。我们使用PROD-ATAC同时检测&；gt；40种小分子抑制剂在单次分析中针对数十种混淆（包括大多数患者鉴定的导致尤文氏肉瘤的融合序列），产生全基因组染色质可及性数据集，代表了&；gt；1000种独特的药物融合相互作用。通过这种方式，我们将几种小分子描述为先前未识别的多种混淆抑制剂。某些抑制剂被发现可以消除由全局或靶向细胞信号通路特异性方式引起的混乱引起的染色质失调。通过分析导致相同癌症的多种罕见融合，我们确定了与不同融合蛋白相关的染色质失调的同质和异质模式的单独实例。在这项工作中，PROD-ATAC染色质可接近性读数将鉴定新的混淆抑制剂与表征每种抑制剂对表达混淆细胞的表观遗传景观的影响结合起来。引用格式：James E. Corban, Max Frenkel, Srivatsan Raman。高通量表征抑制剂对混淆诱导的染色质失调的影响[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): nr A024。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-lt004
Alisha Kardian, Hua Sun, Stephen Mack
Introduction ZFTA-RELA (ZR) is the most recurrent genetic alteration seen in pediatric supratentorial ependymoma (EPN) and is sufficient to initiate tumors in mice. Despite the oncogenic potential of ZR, it is observed nearly exclusively in childhood EPN, with tumors located distinctly in the supratentorial region of the central nervous system (CNS). We hypothesized that specific chromatin modules accessible during brain development would render distinct cell lineage programs at direct risk of transformation by ZR. Methods To this end, we performed combined single nucleus ATAC and RNA (snMultiome) sequencing of the developing mouse forebrain, as compared to ZR-driven mouse and human EPN. Results We demonstrate that specific developmental lineage programs present in transient progenitor cells and regulated by PLAG/L family transcription factors (TF) are at risk of neoplastic transformation. Binding of this chromatin network by ZR or other PLAG/L family motif targeting fusion oncoproteins lead to persistent chromatin accessibility at oncogenic loci and oncogene expression. Cross-species analysis of mouse and human ZR EPN reveals significant cell type heterogeneity mirroring incomplete neurogenic and gliogenic differentiation, with a small percentage of cycling progenitor-like or radial glial-like cells that establish a putative tumor cell hierarchy. In vivo lineage tracing studies reveal neoplastic clones that aggressively dominate tumor growth and establish the entire EPN cellular hierarchy. Conclusions These findings unravel developmental epigenomic states critical for fusion oncoprotein-driven transformation and elucidate how these states continue to shape tumor progression. Citation Format: Alisha Kardian, Hua Sun, Stephen Mack. Dominant Malignant Clones Leverage Lineage Restricted Epigenomic Programs to Drive Ependymoma Development [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr LT004.
zfa - rela （ZR）是儿童幕上室管膜瘤（EPN）中最常见的基因改变，足以在小鼠中引发肿瘤。尽管ZR具有致癌潜力，但它几乎只在儿童EPN中观察到，肿瘤明显位于中枢神经系统（CNS）的幕上区域。我们假设大脑发育过程中可获得的特定染色质模块将使不同的细胞谱系程序面临ZR转化的直接风险。为此，我们对发育中的小鼠前脑进行了单核ATAC和RNA （snMultiome）联合测序，并与zr驱动的小鼠和人类EPN进行了比较。结果我们证明了瞬时祖细胞中存在的特定发育谱系程序，并受PLAG/L家族转录因子（TF）的调控，具有肿瘤转化的风险。ZR或其他靶向融合癌蛋白的PLAG/L家族基序结合该染色质网络，导致染色质在致癌位点和癌基因表达上的持续可及性。小鼠和人类ZR EPN的跨物种分析显示，细胞类型异质性显著，反映了不完全的神经源性和胶质源性分化，有一小部分循环祖细胞样细胞或放射状胶质样细胞建立了假定的肿瘤细胞等级。体内谱系追踪研究揭示了肿瘤克隆积极主导肿瘤生长并建立了整个EPN细胞等级。这些发现揭示了对融合癌蛋白驱动转化至关重要的发育表观基因组状态，并阐明了这些状态如何继续塑造肿瘤进展。引文格式：Alisha Kardian， Hua Sun, Stephen Mack。显性恶性克隆利用谱系限制表观基因组程序驱动室管膜瘤的发展[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): nr LT004。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-b024
Constance Pirson, Ariane Sablon, Axelle Loriot, Pierre Autin, A. Koen Braat, Marie Karanian, Cristina R. Antonescu, Franck Tirode, Jean-Baptiste Demoulin
SRF fusion genes drive the pathogenesis of muscle-related soft tissue tumors, including subsets of perivascular tumors, inflammatory myofibroblastic tumor, and rhabdomyosarcoma. SRF encodes Serum Response Factor, a well-characterized transcription factor that regulates muscle development. We characterized four fusion genes: SRF::RELA, SRF::FOXO1, SRF::ICA1L, and SRF::PDGFRB. All localized to the nucleus and dimerized through the SRF MADS box. SRF::RELA, SRF::FOXO1, and SRF::ICA1L acted as constitutively active transcription factors independent of canonical cofactors, binding SRF target promoters and driving transcription via the partner transactivation domain (TAD). A cryptic TAD was uncovered in ICA1L. These fusions promoted mesenchymal cell growth and upregulated muscle-related genes in mesenchymal stem cells, recapitulating transcriptional signatures of human tumors. In contrast, SRF::PDGFRB acted through its kinase domain, was imatinib-sensitive, activated STAT1 and stimulated inflammation genes, consistent with its tumor phenotype. SRF fusions thus define a novel family of oncogenes in human myoid soft tissue tumors. Citation Format: Constance Pirson, Ariane Sablon, Axelle Loriot, Pierre Autin, A. Koen Braat, Marie Karanian, Cristina R. Antonescu, Franck Tirode, Jean-Baptiste Demoulin. SRF fusion oncogenes encode constitutively activated chimeric transcription factors in myoid soft tissue tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr B024.
SRF融合基因驱动肌肉相关软组织肿瘤的发病机制，包括血管周围肿瘤亚群、炎症性肌纤维母细胞肿瘤和横纹肌肉瘤。SRF编码血清反应因子，这是一种具有良好特征的调节肌肉发育的转录因子。我们鉴定了四个融合基因：SRF::RELA、SRF:: fox01、SRF::ICA1L和SRF::PDGFRB。全部定位于细胞核并通过SRF MADS盒子进行二聚化。SRF::RELA、SRF:: fox01和SRF::ICA1L作为独立于典型辅因子的组成型活性转录因子，结合SRF靶启动子并通过伴侣转激活域（TAD）驱动转录。在ICA1L中发现了一个神秘的TAD。这些融合促进了间充质细胞的生长，上调了间充质干细胞中的肌肉相关基因，重现了人类肿瘤的转录特征。相比之下，SRF::PDGFRB通过其激酶结构域起作用，对伊马替尼敏感，激活STAT1并刺激炎症基因，与其肿瘤表型一致。因此，SRF融合在人肌样软组织肿瘤中定义了一个新的癌基因家族。引文格式：Constance Pirson， Ariane Sablon, Axelle Loriot, Pierre Autin， A. Koen Braat, Marie Karanian, Cristina R. Antonescu, Franck Tirode, Jean-Baptiste Demoulin。SRF融合癌基因编码构成型激活嵌合转录因子在肌样软组织肿瘤[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): nr B024。
{"title":"Abstract B024: SRF fusion oncogenes encode constitutively activated chimeric transcription factors in myoid soft tissue tumors","authors":"Constance Pirson, Ariane Sablon, Axelle Loriot, Pierre Autin, A. Koen Braat, Marie Karanian, Cristina R. Antonescu, Franck Tirode, Jean-Baptiste Demoulin","doi":"10.1158/1538-7445.fusionpositive26-b024","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-b024","url":null,"abstract":"SRF fusion genes drive the pathogenesis of muscle-related soft tissue tumors, including subsets of perivascular tumors, inflammatory myofibroblastic tumor, and rhabdomyosarcoma. SRF encodes Serum Response Factor, a well-characterized transcription factor that regulates muscle development. We characterized four fusion genes: SRF::RELA, SRF::FOXO1, SRF::ICA1L, and SRF::PDGFRB. All localized to the nucleus and dimerized through the SRF MADS box. SRF::RELA, SRF::FOXO1, and SRF::ICA1L acted as constitutively active transcription factors independent of canonical cofactors, binding SRF target promoters and driving transcription via the partner transactivation domain (TAD). A cryptic TAD was uncovered in ICA1L. These fusions promoted mesenchymal cell growth and upregulated muscle-related genes in mesenchymal stem cells, recapitulating transcriptional signatures of human tumors. In contrast, SRF::PDGFRB acted through its kinase domain, was imatinib-sensitive, activated STAT1 and stimulated inflammation genes, consistent with its tumor phenotype. SRF fusions thus define a novel family of oncogenes in human myoid soft tissue tumors. Citation Format: Constance Pirson, Ariane Sablon, Axelle Loriot, Pierre Autin, A. Koen Braat, Marie Karanian, Cristina R. Antonescu, Franck Tirode, Jean-Baptiste Demoulin. SRF fusion oncogenes encode constitutively activated chimeric transcription factors in myoid soft tissue tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr B024.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"14 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962068","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 : 2026-01-13DOI: 10.1158/0008-5472.can-25-1720
Surendra Gulla,Tej Sharma,Ephraim Gardner,Chennan Li,Tanaya A Purohit,Chao Xue,Sean Colligan,Shreya Shyam Sundar,Bing Yang,Shana Y Trostel,Brian Capaldo,Jonathan E Bard,Tobilola Ogunbowale,Abbas Jawadwala,Min Ma,Jun Qu,Fatima Karzai,Roberto Pili,David F Jarrard,Adam G Sowalsky,David J VanderWeele,Remi Adelaiye-Ogala
Reprogramming of the androgen receptor (AR) cistrome is associated with prostate cancer progression, and advanced castrate-resistant prostate cancers (CRPC) tend to rely on reprogrammed/non-canonical AR signaling that remains active under treatment with AR signaling inhibitors (ARSI). Here, we identified EVI1, an oncogenic nuclear transcription factor encoded by MECOM, as an AR-recruited co-activator of non-canonical signaling. In prostate cancer, MECOM was exclusively overexpressed in both CRPC and enzalutamide-resistant CRPC and interacted with AR in the nucleus. MECOM depletion in prostate cancer cells decreased proliferation, altered cell survival transcriptional programs, and reduced the number of super-enhancers (SEs), leading to a dynamic change in the SE landscape and a decrease in the expression of SE-regulated oncogenic transcription factors, along with increased pro-apoptotic signatures. Notably, cells overexpressing MECOM and its protein, EVI1, were susceptible to PARP inhibitors regardless of their DNA damage response or homologous recombination repair (HRR) gene mutation status. These insights reveal the crucial role of EVI1 in regulating cell survival within the context of an AR-reprogrammed chromatin landscape. More importantly, the findings suggest that MECOM overexpression may be another biomarker that could significantly broaden the use of PARP inhibitors beyond those with HRR gene mutations.
{"title":"MECOM Function is Critical for AR-Driven Treatment-Resistant Prostate Cancer.","authors":"Surendra Gulla,Tej Sharma,Ephraim Gardner,Chennan Li,Tanaya A Purohit,Chao Xue,Sean Colligan,Shreya Shyam Sundar,Bing Yang,Shana Y Trostel,Brian Capaldo,Jonathan E Bard,Tobilola Ogunbowale,Abbas Jawadwala,Min Ma,Jun Qu,Fatima Karzai,Roberto Pili,David F Jarrard,Adam G Sowalsky,David J VanderWeele,Remi Adelaiye-Ogala","doi":"10.1158/0008-5472.can-25-1720","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-1720","url":null,"abstract":"Reprogramming of the androgen receptor (AR) cistrome is associated with prostate cancer progression, and advanced castrate-resistant prostate cancers (CRPC) tend to rely on reprogrammed/non-canonical AR signaling that remains active under treatment with AR signaling inhibitors (ARSI). Here, we identified EVI1, an oncogenic nuclear transcription factor encoded by MECOM, as an AR-recruited co-activator of non-canonical signaling. In prostate cancer, MECOM was exclusively overexpressed in both CRPC and enzalutamide-resistant CRPC and interacted with AR in the nucleus. MECOM depletion in prostate cancer cells decreased proliferation, altered cell survival transcriptional programs, and reduced the number of super-enhancers (SEs), leading to a dynamic change in the SE landscape and a decrease in the expression of SE-regulated oncogenic transcription factors, along with increased pro-apoptotic signatures. Notably, cells overexpressing MECOM and its protein, EVI1, were susceptible to PARP inhibitors regardless of their DNA damage response or homologous recombination repair (HRR) gene mutation status. These insights reveal the crucial role of EVI1 in regulating cell survival within the context of an AR-reprogrammed chromatin landscape. More importantly, the findings suggest that MECOM overexpression may be another biomarker that could significantly broaden the use of PARP inhibitors beyond those with HRR gene mutations.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"54 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961329","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 : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-b016
Chamithi Karunanayake, Hayden Statmore, Ehsan Akbari, Alexi Tallan, Frederic Barr, Michael G. Poirier, Benjamin Stanton
Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue cancer, with approximately 350 cases per year in the US. The highly aggressive tumor subtype, Fusion-Positive Rhabdomyosarcoma (FP-RMS) is characterized by chromosomal translocations yielding oncogenic fusion transcription factors (TFs). The most common RMS fusion (PAX3::FOXO1) forms an in-frame chimera of the DNA-binding domain of PAX3 with the activator domain of FOXO1. We hypothesize that understanding the precise mechanisms of PAX3::FOXO1’s chromatin engagement and nucleosome invasion would enable precision therapy to target these mechanisms to ultimately improve patient outcomes. Our studies are providing evidence that PAX3::FOXO1 has pioneer activity, including nucleosome engagement, and an ability to recognize multiple chromatin states including both open and repressive chromatin regions. We are investigating the biochemical regulatory functions of PAX3::FOXO1 binding to specific DNA motifs embedded within chromatin or nucleosomes, developing synthetic epigenetics to investigate motifs from our genomics-scale studies. We are interested in the preservation of naturally occurring post-translational modifications from the mammalian cellular context, and have sought to build a highly versatile system for investigation of TF/nucleosome targeting from cell extracts. In our studies, we are finding new evidence for PAX3::FOXO1’s targeting of homeodomain and paired domain DNA motifs in free DNA and also in a nucleosome context. We are validating these findings through parallel approaches including coupling electrophoretic mobility shift assays (EMSAs) with westerns and antibody-targeting of complexes within EMSA experiments. We are finding that PAX3::FOXO1’s binding to high-complexity motifs, conjoining paired domain and homeodomain sequences, occurs during nucleosome invasion. Through iterative comparisons, custom unmodified mono-nucleosomes containing three major classes of DNA binding motifs reveal PAX3::FOXO1’s binding to these nucleosomes without a strong motif preference within the categories examined in our series. These findings support a mechanistic hypothesis where PAX3::FOXO1 may invade nucleosomes, altering their local positioning prior to generation of chromatin accessibility. Additional investigations are underway to unravel these mechanisms further and probe the contexts for motif specificity or generality in nucleosome engagement, and to understand conformational changes in the target nucleosomes. The mechanisms we are uncovering will contribute to the search for new therapeutic vulnerabilities as our community progresses toward targeted therapies for FP-RMS. Citation Format: Chamithi Karunanayake, Hayden Statmore, Ehsan Akbari, Alexi Tallan, Frederic Barr, Michael G. Poirier, Benjamin Stanton. Biochemical mechanisms of PAX3::FOXO1 chromatin invasion in Rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer:
横纹肌肉瘤（RMS）是一种侵袭性儿童软组织癌，在美国每年约有350例。融合阳性横纹肌肉瘤（FP-RMS）是一种高度侵袭性的肿瘤亚型，其特征是染色体易位产生致癌融合转录因子（TFs）。最常见的RMS融合（PAX3::FOXO1）形成PAX3的dna结合域与FOXO1的激活域的框内嵌合体。我们假设，了解PAX3::FOXO1染色质结合和核小体入侵的精确机制，将有助于针对这些机制进行精确治疗，最终改善患者的预后。我们的研究提供了证据，证明PAX3:: fox01具有先锋活性，包括核小体参与，以及识别多种染色质状态的能力，包括开放和抑制染色质区域。我们正在研究PAX3::FOXO1与嵌入染色质或核小体中的特定DNA基序结合的生化调节功能，并开发合成表观遗传学来研究基因组学规模的基序。我们对保存哺乳动物细胞环境中自然发生的翻译后修饰很感兴趣，并试图建立一个高度通用的系统来研究细胞提取物中的TF/核小体靶向。在我们的研究中，我们正在寻找新的证据，证明PAX3::FOXO1在游离DNA和核小体中靶向同源结构域和配对结构域DNA基序。我们正在通过平行方法验证这些发现，包括将电泳迁移率转移试验（EMSA）与western和EMSA实验中复合物的抗体靶向结合。我们发现PAX3::FOXO1与高复杂性基序的结合，结合成对结构域和同源结构域序列，发生在核小体入侵过程中。通过反复比较，包含三大类DNA结合基序的定制的未修饰的单核小体揭示了PAX3::FOXO1与这些核小体的结合，在我们的系列研究中没有强烈的基序偏好。这些发现支持了一种机制假说，即PAX3:: fox01可能侵入核小体，在染色质可及性产生之前改变核小体的局部定位。进一步的研究正在进行中，以进一步揭示这些机制，探索核小体结合中基序特异性或普遍性的背景，并了解目标核小体的构象变化。随着我们的社区在FP-RMS的靶向治疗方面取得进展，我们正在发现的机制将有助于寻找新的治疗脆弱性。引文格式：Chamithi Karunanayake， Hayden Statmore, Ehsan Akbari, Alexi Tallan, Frederic Barr, Michael G. Poirier, Benjamin Stanton。横纹肌肉瘤PAX3:: fox01染色质侵袭的生化机制[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): no B016。
{"title":"Abstract B016: Biochemical mechanisms of PAX3::FOXO1 chromatin invasion in Rhabdomyosarcoma","authors":"Chamithi Karunanayake, Hayden Statmore, Ehsan Akbari, Alexi Tallan, Frederic Barr, Michael G. Poirier, Benjamin Stanton","doi":"10.1158/1538-7445.fusionpositive26-b016","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-b016","url":null,"abstract":"Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue cancer, with approximately 350 cases per year in the US. The highly aggressive tumor subtype, Fusion-Positive Rhabdomyosarcoma (FP-RMS) is characterized by chromosomal translocations yielding oncogenic fusion transcription factors (TFs). The most common RMS fusion (PAX3::FOXO1) forms an in-frame chimera of the DNA-binding domain of PAX3 with the activator domain of FOXO1. We hypothesize that understanding the precise mechanisms of PAX3::FOXO1’s chromatin engagement and nucleosome invasion would enable precision therapy to target these mechanisms to ultimately improve patient outcomes. Our studies are providing evidence that PAX3::FOXO1 has pioneer activity, including nucleosome engagement, and an ability to recognize multiple chromatin states including both open and repressive chromatin regions. We are investigating the biochemical regulatory functions of PAX3::FOXO1 binding to specific DNA motifs embedded within chromatin or nucleosomes, developing synthetic epigenetics to investigate motifs from our genomics-scale studies. We are interested in the preservation of naturally occurring post-translational modifications from the mammalian cellular context, and have sought to build a highly versatile system for investigation of TF/nucleosome targeting from cell extracts. In our studies, we are finding new evidence for PAX3::FOXO1’s targeting of homeodomain and paired domain DNA motifs in free DNA and also in a nucleosome context. We are validating these findings through parallel approaches including coupling electrophoretic mobility shift assays (EMSAs) with westerns and antibody-targeting of complexes within EMSA experiments. We are finding that PAX3::FOXO1’s binding to high-complexity motifs, conjoining paired domain and homeodomain sequences, occurs during nucleosome invasion. Through iterative comparisons, custom unmodified mono-nucleosomes containing three major classes of DNA binding motifs reveal PAX3::FOXO1’s binding to these nucleosomes without a strong motif preference within the categories examined in our series. These findings support a mechanistic hypothesis where PAX3::FOXO1 may invade nucleosomes, altering their local positioning prior to generation of chromatin accessibility. Additional investigations are underway to unravel these mechanisms further and probe the contexts for motif specificity or generality in nucleosome engagement, and to understand conformational changes in the target nucleosomes. The mechanisms we are uncovering will contribute to the search for new therapeutic vulnerabilities as our community progresses toward targeted therapies for FP-RMS. Citation Format: Chamithi Karunanayake, Hayden Statmore, Ehsan Akbari, Alexi Tallan, Frederic Barr, Michael G. Poirier, Benjamin Stanton. Biochemical mechanisms of PAX3::FOXO1 chromatin invasion in Rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"57 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961891","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 : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-a003
Yuzhi Gao, David Gonzalez-Martinez, Sofia Wissert, Hana Bader, Nidhi Sahni, Anh Le, Robert Doebele, Lukasz Bugaj
Regulation of cancer cells by their environment contributes to tumorigenesis and drug response, though the extent to which the oncogenic state can alter a cell’s perception of its environment is not clear. EML4-ALK is a receptor tyrosine kinase (RTK) fusion oncoprotein that suppresses transmembrane EGFR signaling in cancer cells. ALK inhibition restores signaling through EGFR, thereby promoting survival and drug tolerance. Here we tested whether such modulation of EGFR activity was common among other RTK fusions, which collectively are found in ∼5% of all cancers. Using live- and fixed-cell microscopy in isogenic and patient-derived cell lines, we found that a wide variety of RTK-fusions suppress transmembrane EGFR and sequester essential adaptor proteins in the cytoplasm, as evidenced by the localization of endogenous Grb2. Targeted therapies rapidly released Grb2 from sequestration and potently reactivated EGFR. Engineered optogenetic analogs of RTK fusions confirmed that cytoplasmic sequestration of Grb2 was sufficient to suppress perception of extracellular EGF and could do so independent of driving signaling from the optogenetic fusion itself, demonstrating that fusion signaling and suppression of EGFR could be functionally decoupled. Our study uncovers that a large number of RTK fusions simultaneously act as both activators and suppressors of signaling, the mechanisms of which could be exploited for new biomimetic therapies that enhance cell killing and suppress drug tolerance. Citation Format: Yuzhi Gao, David Gonzalez-Martinez, Sofia Wissert, Hana Bader, Nidhi Sahni, Anh Le, Robert Doebele, Lukasz Bugaj. Adaptor sequestration and drug-induced potentiation of EGFR are widespread features of oncogenic RTK fusions [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr A003.
环境对癌细胞的调节有助于肿瘤发生和药物反应，尽管致癌状态可以在多大程度上改变细胞对环境的感知尚不清楚。EML4-ALK是一种受体酪氨酸激酶（RTK）融合癌蛋白，可抑制癌细胞中的跨膜EGFR信号传导。ALK抑制通过EGFR恢复信号，从而促进生存和药物耐受性。在这里，我们测试了EGFR活性的这种调节在其他RTK融合中是否常见，这些RTK融合在所有癌症的约5%中被发现。通过对等基因和患者来源的细胞系进行活细胞和固定细胞显微镜观察，我们发现多种rtk融合物抑制跨膜EGFR并隔离细胞质中必需的衔接蛋白，内源性Grb2的定位证明了这一点。靶向治疗可迅速释放Grb2，并有效地重新激活EGFR。RTK融合的工程光遗传类似物证实，细胞质中Grb2的隔离足以抑制细胞外EGF的感知，并且可以独立于光遗传融合本身的驱动信号，这表明融合信号和EGFR的抑制可以在功能上解耦。我们的研究发现，大量的RTK融合体同时作为信号的激活剂和抑制剂，其机制可以用于新的仿生疗法，增强细胞杀伤和抑制药物耐受性。引文格式：Yuzhi Gao， David Gonzalez-Martinez, Sofia Wissert, Hana Bader, Nidhi Sahni, Anh Le, Robert Doebele, Lukasz Bugaj。受体隔离和药物诱导的EGFR增强是致癌RTK融合的普遍特征[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): nr A003。
{"title":"Abstract A003: Adaptor sequestration and drug-induced potentiation of EGFR are widespread features of oncogenic RTK fusions","authors":"Yuzhi Gao, David Gonzalez-Martinez, Sofia Wissert, Hana Bader, Nidhi Sahni, Anh Le, Robert Doebele, Lukasz Bugaj","doi":"10.1158/1538-7445.fusionpositive26-a003","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-a003","url":null,"abstract":"Regulation of cancer cells by their environment contributes to tumorigenesis and drug response, though the extent to which the oncogenic state can alter a cell’s perception of its environment is not clear. EML4-ALK is a receptor tyrosine kinase (RTK) fusion oncoprotein that suppresses transmembrane EGFR signaling in cancer cells. ALK inhibition restores signaling through EGFR, thereby promoting survival and drug tolerance. Here we tested whether such modulation of EGFR activity was common among other RTK fusions, which collectively are found in ∼5% of all cancers. Using live- and fixed-cell microscopy in isogenic and patient-derived cell lines, we found that a wide variety of RTK-fusions suppress transmembrane EGFR and sequester essential adaptor proteins in the cytoplasm, as evidenced by the localization of endogenous Grb2. Targeted therapies rapidly released Grb2 from sequestration and potently reactivated EGFR. Engineered optogenetic analogs of RTK fusions confirmed that cytoplasmic sequestration of Grb2 was sufficient to suppress perception of extracellular EGF and could do so independent of driving signaling from the optogenetic fusion itself, demonstrating that fusion signaling and suppression of EGFR could be functionally decoupled. Our study uncovers that a large number of RTK fusions simultaneously act as both activators and suppressors of signaling, the mechanisms of which could be exploited for new biomimetic therapies that enhance cell killing and suppress drug tolerance. Citation Format: Yuzhi Gao, David Gonzalez-Martinez, Sofia Wissert, Hana Bader, Nidhi Sahni, Anh Le, Robert Doebele, Lukasz Bugaj. Adaptor sequestration and drug-induced potentiation of EGFR are widespread features of oncogenic RTK fusions [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr A003.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"46 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962070","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 : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-a004
Jamie D. Barber, Barbara Van Hare, Naomi Natale, Michael Casaus
Myoepithelial carcinoma (MEC) is an ultra-rare malignancy, with an incidence of 0.013/100,000, characterized by aggressive clinical behavior and the absence of established therapies. MEC can affect adult and pediatric populations, with adult disease more commonly seen in the salivary gland and pediatric disease more commonly seen in soft tissues. In pediatric cases, recurrent gene fusions—most frequently involving EWSR1 with partners such as KLF15—define MEC as a fusion-driven cancer. Despite this, progress has been impeded by limited biospecimen availability, lack of coordinated research infrastructure, and absence of validated preclinical models. To address these barriers, cureMEC: The Myoepithelial Carcinoma Project was established in 2022 as a patient-driven nonprofit dedicated to advancing translational research in MEC. In collaboration with the Rare Cancer Research Foundation (RCRF) and Pattern.org, cureMEC has developed the first dedicated MEC biorepository and integrated data platform, enabling specimen collection, molecular profiling, and open research access. Through strategic partnerships, MEC samples are now included in large-scale fusion-cancer initiatives encompassing transcriptomics, proteomics, and drug-screening pipelines. Early efforts have yielded the first coordinated biobanking network for MEC, capturing clinically annotated specimens across multiple institutions, including at least 75 cases so far. Two novel MEC cell lines and a patient-derived xenograft (PDX) model have been generated and molecularly validated for EWSR1-KLF15 and related fusions. These models will be used to validate EWSR1-KLF15 as a recurrent fusion in MEC and will be probed for differential surface-protein expression patterns that may represent potential therapeutic targets. Parallel high-throughput drug-repurposing studies are being launched to assess sensitivity patterns across fusion-defined models. cureMEC is establishing the first integrated research ecosystem for MEC, centered on fusion biology and patient partnership. By coupling coordinated biospecimen infrastructure with proteogenomic discovery, this initiative is creating essential tools to elucidate MEC pathogenesis and accelerate the development of targeted therapies. This model demonstrates how patient-driven collaborations can rapidly advance research for fusion-positive rare cancers and catalyze progress toward clinical translation. Citation Format: Jamie D. Barber, Barbara Van Hare, Naomi Natale, Michael Casaus. Establishing the First Integrated Research Infrastructure and Preclinical Models for EWSR1 Fusion-Positive Myoepithelial Carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr A004.
肌上皮癌（MEC）是一种极其罕见的恶性肿瘤，发病率为0.013/100,000，其特点是具有侵袭性的临床行为和缺乏成熟的治疗方法。MEC可影响成人和儿科人群，成人疾病更常见于唾液腺，儿科疾病更常见于软组织。在儿科病例中，复发性基因融合-最常见的是涉及EWSR1与伴侣如klf15 -将MEC定义为融合驱动型癌症。尽管如此，有限的生物标本可用性、缺乏协调的研究基础设施以及缺乏经过验证的临床前模型阻碍了进展。为了解决这些障碍，cureMEC：肌上皮癌项目于2022年成立，是一个以患者为导向的非营利组织，致力于推进MEC的转化研究。cureMEC与罕见癌症研究基金会（RCRF）和Pattern.org合作，开发了第一个专用的MEC生物库和集成数据平台，实现标本收集、分子分析和开放研究访问。通过战略合作伙伴关系，MEC样本现在被纳入大规模融合癌计划，包括转录组学、蛋白质组学和药物筛选管道。早期的努力已经产生了MEC的第一个协调生物银行网络，从多个机构捕获临床注释标本，迄今为止包括至少75例病例。两种新的MEC细胞系和患者来源的异种移植（PDX）模型已经生成，并对EWSR1-KLF15和相关融合进行了分子验证。这些模型将用于验证EWSR1-KLF15在MEC中的复发性融合，并将探索可能代表潜在治疗靶点的不同表面蛋白表达模式。正在开展平行的高通量药物再利用研究，以评估融合定义模型的敏感性模式。cureMEC正在建立首个以融合生物学和患者合作为中心的MEC综合研究生态系统。通过将协调的生物标本基础设施与蛋白质基因组学发现相结合，该计划正在创造必要的工具来阐明MEC的发病机制并加速靶向治疗的发展。该模型展示了患者驱动的合作如何能够快速推进融合阳性罕见癌症的研究，并催化临床转化的进展。引文格式：Jamie D. Barber, Barbara Van Hare, Naomi Natale, Michael Casaus。建立EWSR1融合阳性肌上皮癌的首个综合研究基础设施和临床前模型[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): nr A004。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-ia006
Ross A. Okimoto, Padmini Bisoyi, Rovingaile Kriska Ponce, Nicholas Thomas
Capicua (CIC) rearranged sarcomas are a rare but lethal group of soft-tissue sarcomas most commonly found in pediatric and adolescence and young adults (AYA). The most well-characterized CIC-rearrangement is the prototypical CIC::DUX4 fusion oncoprotein, which currently has no effective therapies and is associated with dismal clinical outcomes. Using rare patient-derived CIC::DUX4 cells we recently identified a molecular dependence on the CCNE/CDK2 complex in CIC::DUX4 sarcoma, whereby the CIC::DUX4 oncoprotein transcriptionally upregulates CCNE1 to drive sarcoma growth and survival. Mechanistically, increased CCNE1expression through transcriptional upregulation compromises the G1/S transition to enhance DNA replication stress and genomic instability. Cancer cells adapt to these high replication stress states through increased dependence on cell-cycle checkpoints that enable replication stalling and DNA repair. Consistent with this, we recently defined the G2/M checkpoint kinase, WEE1 as a key regulator of mitotic entry and survival in CIC::DUX4 sarcomas. WEE1 inhibition releases the G2/M break and allows premature mitotic entry and subsequent death through irreversible DNA damage and mitotic catastrophe. We will discuss strategies to pharmacologically exploit this CCNE1 mediated high replication stress state through combinatorial drug approaches that augment replication stress and/or co-target the G2/M checkpoint in CIC-rearranged cancers. Citation Format: Ross A. Okimoto, Padmini Bisoyi, Rovingaile Kriska Ponce, Nicholas Thomas. Targeting replication stress and cell-cycle checkpoints to overcome CIC-rearranged sarcomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr IA006.
Capicua （CIC）重排肉瘤是一种罕见但致命的软组织肉瘤，最常见于儿科、青少年和年轻人（AYA）。最具特征的CIC重排是典型的CIC::DUX4融合癌蛋白，目前尚无有效的治疗方法，且临床结果不佳。利用罕见的患者来源的CIC::DUX4细胞，我们最近发现CIC::DUX4肉瘤对CCNE/CDK2复合物的分子依赖性，CIC::DUX4癌蛋白通过转录上调CCNE1来驱动肉瘤的生长和存活。从机制上讲，通过转录上调ccne1表达的增加会损害G1/S过渡，从而增强DNA复制压力和基因组不稳定性。癌细胞通过增加对细胞周期检查点的依赖来适应这些高复制应激状态，从而使复制停滞和DNA修复。与此一致，我们最近将G2/M检查点激酶WEE1定义为CIC::DUX4肉瘤有丝分裂进入和存活的关键调节因子。WEE1抑制释放G2/M断裂，通过不可逆的DNA损伤和有丝分裂灾难导致有丝分裂过早进入和随后的死亡。我们将讨论利用CCNE1介导的高复制应激状态的药理学策略，通过组合药物方法增加复制应激和/或共同靶向cic重排癌症的G2/M检查点。引文格式：Ross A. Okimoto, Padmini Bisoyi, Rovingaile Kriska Ponce, Nicholas Thomas。靶向复制应激和细胞周期检查点克服cic重排肉瘤[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_supl): nr IA006。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-a007
Shu Zhang, Hyerim Yi, Jason Swinderman, Yanbo Wang, Vishnupriya Kanakaviti, King L. Hung, Ivy Tsz-Lo. Wong, Suhas Srinivasan, Ellis J. Curtis, Aarohi Bhargava-Shah, Rui Li, Matthew G. Jones, Jens Luebeck, Chris Bailey, Yanding Zhao, Julia A. Belk, Katerina Kraft, Quanming Shi, Xiaowei Yan, Simon K. Pritchard, Kabir S. Mahajan, Frances Liang, Mariam Jamal-Hanjani, Dean W. Felsher, Luke A. Gilbert, Vineet Bafna, Paul S. Mischel, Howard Y. Chang
Extrachromosomal DNA (ecDNA) amplifications are key drivers of human cancers. Here, we show that ecDNAs are major platforms for generating and amplifying oncogene fusion transcripts across diverse cancer types. By integrating analysis of whole genome and transcriptome sequences from 1,825 tumor samples and cancer cell lines of a wide variety of tissue types, we reveal that ecDNAs have the highest rate of oncogene fusion events of any copy number alteration. Focusing on the most common ecDNA fusion hotspot, we find that fusion of the 5' end of the long noncoding RNA gene, PVT1–with exon 1 joined to diverse 3' partners–confers increased RNA stability, and enhances MYC-dependent transcription and cancer cell survival. These results demonstrate that ecDNA fosters genome instability and frequent oncogene fusion formation under strong selection in cancer. Citation Format: Shu Zhang, Hyerim Yi, Jason Swinderman, Yanbo Wang, Vishnupriya Kanakaviti, King L. Hung, Ivy Tsz-Lo. Wong, Suhas Srinivasan, Ellis J. Curtis, Aarohi Bhargava-Shah, Rui Li, Matthew G. Jones, Jens Luebeck, Chris Bailey, Yanding Zhao, Julia A. Belk, Katerina Kraft, Quanming Shi, Xiaowei Yan, Simon K. Pritchard, Kabir S. Mahajan, Frances Liang, Mariam Jamal-Hanjani, Dean W. Felsher, Luke A. Gilbert, Vineet Bafna, Paul S. Mischel, Howard Y. Chang. EcDNA-derived structural variants: A common pathway to oncogenic fusion transcript amplification in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr A007.
染色体外DNA （ecDNA）扩增是人类癌症的关键驱动因素。在这里，我们表明ecdna是在不同癌症类型中产生和扩增癌基因融合转录物的主要平台。通过对来自1825个肿瘤样本和各种组织类型的癌细胞系的全基因组和转录组序列的整合分析，我们发现ecdna在任何拷贝数改变中具有最高的癌基因融合事件发生率。关注最常见的ecDNA融合热点，我们发现长链非编码RNA基因pvt1的5‘端（外显子1连接到不同的3’伴侣）的融合增加了RNA稳定性，并增强了myc依赖性转录和癌细胞存活。这些结果表明，在癌症的强选择下，ecDNA促进了基因组的不稳定性和频繁的癌基因融合形成。引用格式：张舒，Hyerim Yi, Jason Swinderman，王彦波，Vishnupriya Kanakaviti, King L. Hung, Ivy Tsz-Lo。Wong, Suhas Srinivasan, Ellis J. Curtis, Aarohi Bhargava-Shah，李锐，Matthew G. Jones, Jens Luebeck, Chris Bailey，赵彦丁，Julia A. Belk, Katerina Kraft，史全明，闫晓伟，Simon K. Pritchard, Kabir S. Mahajan, Frances Liang, Mariam Jamal-Hanjani, Dean W. Felsher, Luke A. Gilbert, Vineet Bafna, Paul S. Mischel, Howard Y. Chang。ecdna衍生的结构变异：癌症中致癌融合转录物扩增的共同途径[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): no A007。
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