Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-b023
Emily Isenhart, Sarah Gawlak, Kristen Humphrey, Michalis Mastri, Scott Olejniczak, Miranda L. Lynch, Joyce Ohm
Chromosomal translocations are commonly harbored in rare mesenchymal cancers known as soft tissue sarcomas (STS). These translocations often result in functional oncogenic fusion proteins which are pathognomonic for some STS. To study the transcriptional consequences of these aberrant chimeras across STS, we performed deep RNA sequencing on 39 patent samples with suspected fusion oncoproteins. Samples are representative of Ewing sarcoma, extraskeletal myxoid chondrosarcoma, clear cell sarcoma, myxoid/round cell liposarcoma, endometrial stromal sarcoma, and synovial sarcoma. Unexpectedly, we identified many unique and shared chimeric RNA across all samples including pathognomonic EWSR1 containing fusions as expected for specific subtypes. In Ewing sarcoma (EwS), EWSR1-FLI1 is the most common diagnostic fusion, which can occur via a balanced or complex translocation. Where a balanced translocation occurs, expression of both the canonical fusion (EWSR1-FLI1) and the reciprocal fusion (FLI1-EWSR1) may be seen. However, relatively little is known about the reciprocal fusion. Upon induction of a reciprocal construct in the EwS cell line A673, we identified differential gene expression of the noncoding RNAs including RN7SK, RN7SL1, RN7SL2, and RPPH1. RN7SK is a small nuclear RNA that regulates gene transcription by interacting with the positive transcription elongation factor b (P-TEFb) and plays a role in stem cell proliferation, differentiation, senescence, and apoptosis. Interestingly, noncoding RNA fusions with RN7SK chimera involving RNA pol III transcripts were the most abundant fusions identified across all STS tumors, though a functional role for these aberrant transcripts has not been defined. Wild type EWSR1 plays a role in RNA splicing, and these data suggest that EwS and EwS fusions may play a role in the regulation of ncRNA fusions and subsequently the disruption of normal RN7SK regulatory function. We aim to evaluate whether ncRNA fusions can also be identified in non-fusion driven sarcomas, at what point such ncRNA fusions may be arising in the central dogma, and what their function may be in sarcomagenesis. Further study regarding the function and consequences of these RNA fusions is required to understand their importance in disease initiation and progression. Citation Format: Emily Isenhart, Sarah Gawlak, Kristen Humphrey, Michalis Mastri, Scott Olejniczak, Miranda L. Lynch, Joyce Ohm. ConFusion: The unexpected presence of non-coding RNA fusions in fusion-positive soft tissue 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 B023.
染色体易位通常存在于被称为软组织肉瘤（STS）的罕见间充质癌中。这些易位通常导致功能性的致癌融合蛋白，这是一些STS的病理特征。为了研究这些异常嵌合体在STS中的转录后果，我们对39个疑似融合癌蛋白的专利样本进行了深度RNA测序。样本包括尤文氏肉瘤、骨外黏液样软骨肉瘤、透明细胞肉瘤、黏液样/圆细胞脂肪肉瘤、子宫内膜间质肉瘤和滑膜肉瘤。出乎意料的是，我们在所有样本中发现了许多独特和共享的嵌合RNA，包括病理表型EWSR1，如预期的那样包含特定亚型的融合。在尤文氏肉瘤（EwS）中，EWSR1-FLI1是最常见的诊断性融合，它可以通过平衡或复杂的易位发生。在发生平衡易位的地方，可以看到典型融合（EWSR1-FLI1）和互惠融合（FLI1-EWSR1）的表达。然而，人们对相互聚变的了解相对较少。通过在EwS细胞系A673中诱导互惠构建，我们发现了RN7SK、RN7SL1、RN7SL2和RPPH1等非编码rna的差异基因表达。RN7SK是一种小核RNA，通过与正转录延伸因子b （P-TEFb）相互作用调节基因转录，在干细胞增殖、分化、衰老和凋亡中发挥作用。有趣的是，涉及RNA pol III转录物的非编码RNA与RN7SK嵌合体的融合是所有STS肿瘤中发现的最丰富的融合，尽管这些异常转录物的功能作用尚未确定。野生型EWSR1在RNA剪接中发挥作用，这些数据表明EwS和EwS融合可能在调节ncRNA融合中发挥作用，进而破坏正常的RN7SK调节功能。我们的目的是评估ncRNA融合是否也可以在非融合驱动型肉瘤中被鉴定出来，在什么时候这种ncRNA融合可能在中心教条中出现，以及它们在肉瘤形成中的功能。需要进一步研究这些RNA融合的功能和后果，以了解它们在疾病发生和进展中的重要性。引文格式：Emily Isenhart， Sarah Gawlak, Kristen Humphrey, Michalis Mastri, Scott Olejniczak, Miranda L. Lynch, Joyce Ohm。混淆：融合阳性软组织肉瘤中意外存在非编码RNA融合物[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 B023。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-pr003
Huibin Yang, Radhika Suhas. Hulbatte, Natalie Gratsch, Ann Urzynicok, Ashley Sutter, Meyer Cusnir, Mario Ashaka, Ishwarya Venkata. Narayanan, Michelle Paulsen, Anna Schwendeman, Tom E. Wilson, Erika Newman, Mats Ljungman
With the development of whole genome sequencing and CRISPR technology, it is now possible to identify sequence features that are unique to an individual’s cancer genome and to precisely target them. Such personalized precision therapy holds the promise of ushering in a new era of safe and effective cancer treatments with minimal side-effects. To specifically target the cancer genome, we have developed a CRISPR-based therapeutic approach, “KLIPP,” which is designed to target structural variants junctions (SVJs) specific to cancer genomes, with few, or no off-target effects expected in normal cell. KLIPP uses a “split enzyme” approach consisting of a dead Cas9 endonuclease (dCas9) fused to the endonuclease Fok1 where two Fok1 endonucleases need to homodimerize to become active. To “nucleate” and activate these complexes, sgRNAs are designed to bind sequences flanking cancer-specific SVJs, bringing two Fok1-dCas9 complexes together to induce double-strand breaks (DSBs). While any SVJ in the cancer genome may be targeted with KLIPP, we have found that junctions in oncogenic fusion genes represents a particularly valuable target. We show effective targeting of the EWS::FLI1 fusion oncogene in Ewing sarcoma cells using lipid nanoparticle delivery of the Fok1-dCas9 mRNA and SVJ-targeting sgRNA, leading to the induction of DSBs, diminished expression of the fusion oncogene and loss of cell survival. Other fusion oncogenes that we are currently targeting with KLIPP involve TMPSS2::ERG in prostate cancer, DNAJB1::PRKACA in fibrolamellar liver cancer and BCR::ABL1 in leukemia. We believe that KLIPP is a safe and cancer-specific approach for precision targeting of fusion oncogenes in cancer cells. This paradigm-shifting personalized therapy could revolutionize how we treat fusion-driven cancers without inflicting long-term side effects. Citation Format: Huibin Yang, Radhika Suhas. Hulbatte, Natalie Gratsch, Ann Urzynicok, Ashley Sutter, Meyer Cusnir, Mario Ashaka, Ishwarya Venkata. Narayanan, Michelle Paulsen, Anna Schwendeman, Tom E. Wilson, Erika Newman, Mats Ljungman. KLIPP: Targeting fusion oncogenes with CRISPR [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 A008.
随着全基因组测序和CRISPR技术的发展，现在有可能识别个体癌症基因组特有的序列特征，并精确地针对它们。这种个性化的精准治疗有望开启一个安全有效、副作用最小的癌症治疗新时代。为了专门针对癌症基因组，我们开发了一种基于crispr的治疗方法“KLIPP”，该方法旨在针对癌症基因组特异性的结构变异连接（svj），在正常细胞中几乎没有脱靶效应。KLIPP使用一种“分裂酶”方法，由死亡的Cas9内切酶（dCas9）融合到内切酶Fok1中，其中两个Fok1内切酶需要同二聚体才能变得活跃。为了“成核”并激活这些复合物，sgrna被设计成结合癌症特异性svj两侧的序列，将两个Fok1-dCas9复合物结合在一起，诱导双链断裂（dsb）。虽然KLIPP可以靶向癌症基因组中的任何SVJ，但我们发现致癌融合基因的连接代表了一个特别有价值的目标。我们发现，通过脂质纳米颗粒递送Fok1-dCas9 mRNA和svj -靶向sgRNA， EWS::FLI1融合癌基因在Ewing肉瘤细胞中有效靶向，导致dsb的诱导，融合癌基因的表达减少，细胞存活丧失。KLIPP目前针对的其他融合癌基因包括前列腺癌中的TMPSS2::ERG，纤维层状肝癌中的DNAJB1::PRKACA和白血病中的BCR::ABL1。我们相信KLIPP是一种安全的癌症特异性方法，可以精确靶向癌细胞中的融合癌基因。这种范式转换的个性化治疗可能会彻底改变我们治疗融合驱动型癌症的方式，而不会造成长期的副作用。引用格式：杨惠斌，Radhika Suhas。Hulbatte, Natalie Gratsch, Ann Urzynicok, Ashley Sutter, Meyer Cusnir, Mario Ashaka, Ishwarya Venkata。Narayanan, Michelle Paulsen, Anna Schwendeman, Tom E. Wilson, Erika Newman, Mats Ljungman。KLIPP：利用CRISPR靶向融合癌基因[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 A008。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-a017
Hesham Mohei, Malay Haldar
Synovial sarcomas (SS) are driven by the SS18-SSX fusion oncogene, generated by the pathognomonic t(X; 18) translocation. In genetically engineered Rosa26LSL-SS18-SSX2 mice, conditional activation of the fusion oncogene in defined lineages, such as the skeletal muscle, leads to tumor formation. However, tissue-specific activation through Cre-driver crosses has notable limitations for tumor modeling, including multifocal tumor induction, difficulty in identifying early lesions, and potential toxicities associated with widespread expression of the fusion oncogene. Local induction of SS in the Rosa26LSL-SS18-SSX2 mice by injecting TAT-CRE protein overcomes some of these limitations but has long and variable tumor latency. To overcome these limitations, we developed a next-generation SS mouse model in which Cre protein is locally delivered via intramuscular injection to simultaneously induce SS18-SSX expression, Pten deletion, and β-catenin activation. This strategy generates tumors at the injection site within three weeks with 100% penetrance. The resulting tumors—and cell lines derived from them—exhibit aggressive growth and faithfully recapitulate the histologic and molecular features of human SS. While SS has traditionally been considered immunologically “cold” due to its low mutation burden, our studies using this model reveal the presence of active immunosuppressive mechanisms that constrain the initiation and propagation of adaptive immune responses. Dissecting and therapeutically targeting these suppressive pathways may therefore provide new avenues for effective immunotherapy in SS. Citation Format: Hesham Mohei, Malay Haldar. A new mouse model of SS18-SSX fusion oncogene driven Synovial 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 A017.
滑膜肉瘤（SS）是由t（X; 18）易位引起的SS18-SSX融合癌基因驱动的。在基因工程Rosa26LSL-SS18-SSX2小鼠中，特定谱系（如骨骼肌）中融合癌基因的条件激活导致肿瘤形成。然而，通过cre驱动交叉的组织特异性激活对肿瘤建模有明显的局限性，包括多灶性肿瘤诱导，难以识别早期病变，以及与融合癌基因广泛表达相关的潜在毒性。通过注射TAT-CRE蛋白在Rosa26LSL-SS18-SSX2小鼠中局部诱导SS克服了这些局限性，但具有较长的可变肿瘤潜伏期。为了克服这些限制，我们开发了下一代SS小鼠模型，通过肌肉注射局部递送Cre蛋白，同时诱导SS18-SSX表达、Pten缺失和β-catenin激活。该策略在三周内以100%的外显率在注射部位产生肿瘤。由此产生的肿瘤和来源于它们的细胞系表现出侵袭性生长，并忠实地再现了人类SS的组织学和分子特征。尽管SS传统上被认为是免疫“冷”的，因为它的低突变负担，我们使用该模型的研究揭示了活性免疫抑制机制的存在，该机制限制了适应性免疫反应的启动和传播。因此，解剖和治疗这些抑制通路可能为SS的有效免疫治疗提供新的途径。SS18-SSX融合癌基因驱动滑膜肉瘤小鼠新模型[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_supl): no A017。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-a015
Cuyler Luck, Ross A. Okimoto
The extreme rarity of certain fusion-oncogene-driven cancers limits dedicated mechanistic study and the potential development of new therapies. Beyond simple expression constructs, only a select few fusion-driven cancers have had synthetic tools engineered which enable complex and thorough biological dissection of these driver events. In this work, we focus on facilitating access to research focused on fusion genes involving capicua (CIC) and ataxin 1 (ATXN1). While prior work from our group and others has led to advances in modeling CIC::DUX4 sarcoma, no tools have existed to study fusions involving other 3’ partners including CIC::NUTM1 and CIC::LEUTX, which have different clinical characteristics compared to CIC::DUX4. We use the first models of CIC::NUTM1 and CIC::LEUTX to evaluate the gene programs they drive and the functional domains they rely on to function. We characterize a novel region within the NUTM1 fragment of CIC::NUTM1, which enables expression of hundreds of genes not strongly induced by CIC::DUX4 in 293T cells. This molecular divergence has potential implications for the identification of the CIC::NUTM1 cell of origin. We also find two LEUTX transactivating domains as key for CIC::LEUTX-mediated transcriptional activation of a CIC target gene, potentially highlighting a therapeutic vulnerability. Finally, we build and characterize the first model of ATXN1 (a known CIC interactor) containing fusions, including ATXN1::DUX4 tumors, which constitute a rare but interesting class of fusions that potentially co-opt native CIC interactions to drive tumorigenesis. Beyond transcriptional events, we have engineered tools to study CIC::DUX4 at the cellular level. Specifically, we developed tools for microscopic visualization (mStayGold tag) and proximity labelling (TurboID tag) of the CIC::DUX4 fusion oncoprotein. These tools will facilitate our understanding of CIC::DUX4-mediated cellular interactions and function, improving our understanding of it to a level comparable to that of the more well studied EWS::FLI or PAX::FOXO fusions. Collectively, we have developed a suite of ready-made tools and model systems to scientifically and clinically advance the study of CIC- and ATXN1-rearranged cancers. A major goal of this project is to provide the research community with CIC and ATXN1 fusion tools and resources to advance therapies and improve outcomes for these devastating and understudied diseases. Citation Format: Cuyler Luck, Ross A. Okimoto. Lowering barriers to studying CIC- and ATXN1-rearranged cancers [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 A015.
某些融合癌基因驱动的癌症极其罕见，限制了专门的机制研究和新疗法的潜在发展。除了简单的表达结构外，只有少数融合驱动的癌症已经有了合成工具，可以对这些驱动事件进行复杂而彻底的生物学解剖。在这项工作中，我们的重点是促进对capicua （CIC）和ataxin 1 （ATXN1）融合基因的研究。虽然我们小组和其他人之前的工作在CIC::DUX4肉瘤建模方面取得了进展，但没有工具来研究涉及其他3 '伴体的融合，包括CIC::NUTM1和CIC::LEUTX，它们与CIC::DUX4具有不同的临床特征。我们使用CIC::NUTM1和CIC::LEUTX的第一个模型来评估它们驱动的基因程序和它们所依赖的功能域。我们描述了CIC::NUTM1片段内的一个新区域，该区域能够在293T细胞中表达数百种不受CIC::DUX4强烈诱导的基因。这种分子分化对CIC::NUTM1细胞起源的鉴定具有潜在的意义。我们还发现两个LEUTX反激活结构域是CIC::LEUTX介导的CIC靶基因转录激活的关键，潜在地突出了CIC的治疗脆弱性。最后，我们建立并表征了第一个包含融合的ATXN1（一种已知的CIC相互作用因子）模型，包括ATXN1::DUX4肿瘤，它们构成了一种罕见但有趣的融合类型，可能会选择天然CIC相互作用来驱动肿瘤发生。除了转录事件，我们还设计了工具在细胞水平上研究CIC::DUX4。具体来说，我们开发了用于CIC::DUX4融合癌蛋白显微可视化（mStayGold标签）和接近标记（TurboID标签）的工具。这些工具将促进我们对CIC:: dux4介导的细胞相互作用和功能的理解，将我们对其的理解提高到与更深入研究的EWS::FLI或PAX::FOXO融合相当的水平。我们共同开发了一套现成的工具和模型系统，以科学和临床地推进CIC和atxn1重排癌症的研究。该项目的一个主要目标是为研究界提供CIC和ATXN1融合工具和资源，以推进这些破坏性和研究不足的疾病的治疗和改善结果。引用格式：Cuyler Luck， Ross A. Okimoto。降低研究CIC和atxn1重排癌症的障碍[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 A015。
{"title":"Abstract A015: Lowering barriers to studying CIC - and ATXN1 -rearranged cancers","authors":"Cuyler Luck, Ross A. Okimoto","doi":"10.1158/1538-7445.fusionpositive26-a015","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-a015","url":null,"abstract":"The extreme rarity of certain fusion-oncogene-driven cancers limits dedicated mechanistic study and the potential development of new therapies. Beyond simple expression constructs, only a select few fusion-driven cancers have had synthetic tools engineered which enable complex and thorough biological dissection of these driver events. In this work, we focus on facilitating access to research focused on fusion genes involving capicua (CIC) and ataxin 1 (ATXN1). While prior work from our group and others has led to advances in modeling CIC::DUX4 sarcoma, no tools have existed to study fusions involving other 3’ partners including CIC::NUTM1 and CIC::LEUTX, which have different clinical characteristics compared to CIC::DUX4. We use the first models of CIC::NUTM1 and CIC::LEUTX to evaluate the gene programs they drive and the functional domains they rely on to function. We characterize a novel region within the NUTM1 fragment of CIC::NUTM1, which enables expression of hundreds of genes not strongly induced by CIC::DUX4 in 293T cells. This molecular divergence has potential implications for the identification of the CIC::NUTM1 cell of origin. We also find two LEUTX transactivating domains as key for CIC::LEUTX-mediated transcriptional activation of a CIC target gene, potentially highlighting a therapeutic vulnerability. Finally, we build and characterize the first model of ATXN1 (a known CIC interactor) containing fusions, including ATXN1::DUX4 tumors, which constitute a rare but interesting class of fusions that potentially co-opt native CIC interactions to drive tumorigenesis. Beyond transcriptional events, we have engineered tools to study CIC::DUX4 at the cellular level. Specifically, we developed tools for microscopic visualization (mStayGold tag) and proximity labelling (TurboID tag) of the CIC::DUX4 fusion oncoprotein. These tools will facilitate our understanding of CIC::DUX4-mediated cellular interactions and function, improving our understanding of it to a level comparable to that of the more well studied EWS::FLI or PAX::FOXO fusions. Collectively, we have developed a suite of ready-made tools and model systems to scientifically and clinically advance the study of CIC- and ATXN1-rearranged cancers. A major goal of this project is to provide the research community with CIC and ATXN1 fusion tools and resources to advance therapies and improve outcomes for these devastating and understudied diseases. Citation Format: Cuyler Luck, Ross A. Okimoto. Lowering barriers to studying CIC- and ATXN1-rearranged cancers [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 A015.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"17 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962074","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 : 2026-01-09DOI: 10.1158/0008-5472.can-25-2126
Jordi Rodon,Melissa L Johnson,Ben George,Pooja A Shah,Kathryn C Arbour
Homozygous deletions in the gene encoding methylthioadenosine phosphorylase (MTAP) occur in ~10% of patients with cancer, including up to 45% in some tumor types, and may be associated with poor prognosis. MTAP deficiency causes accumulation of its catabolic target methylthioadenosine (MTA) that outcompetes S-adenosyl methionine (SAM) for binding to protein arginine methyltransferase 5 (PRMT5), partially inhibiting PRMT5 activity as a posttranslational regulator of a variety of critical cellular functions. Prior anticancer treatments developed to target PRMT5 exhibited high rates of dose-limiting hematologic toxicities because of a lack of selectivity for tumor cells. More recently, several agents have been developed that exploit the vulnerability of MTAP-deleted cancer cells to further inhibition of the PRMT5 pathway, selectively inducing synthetic lethality in those cancer cells. MTA-cooperative PRMT5 inhibitors such as BMS-986504/MRTX1719 and AMG 193 target the PRMT5-MTA complex, while inhibitors of the SAM synthetase methionine adenosyl transferase 2A (MAT2A), such as IDE397, deprive PRMT5 of its methyl donor SAM. In this review article, we summarize the mechanisms of action, preclinical data, and clinical data available thus far for these novel classes of oncology precision medicine and discuss potential future directions relevant to MTAP deletion as a promising synthetic lethal vulnerability for cancer therapy.
{"title":"MTAP Deletion in Oncogenesis: A Synthetic Lethality Scenario.","authors":"Jordi Rodon,Melissa L Johnson,Ben George,Pooja A Shah,Kathryn C Arbour","doi":"10.1158/0008-5472.can-25-2126","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-2126","url":null,"abstract":"Homozygous deletions in the gene encoding methylthioadenosine phosphorylase (MTAP) occur in ~10% of patients with cancer, including up to 45% in some tumor types, and may be associated with poor prognosis. MTAP deficiency causes accumulation of its catabolic target methylthioadenosine (MTA) that outcompetes S-adenosyl methionine (SAM) for binding to protein arginine methyltransferase 5 (PRMT5), partially inhibiting PRMT5 activity as a posttranslational regulator of a variety of critical cellular functions. Prior anticancer treatments developed to target PRMT5 exhibited high rates of dose-limiting hematologic toxicities because of a lack of selectivity for tumor cells. More recently, several agents have been developed that exploit the vulnerability of MTAP-deleted cancer cells to further inhibition of the PRMT5 pathway, selectively inducing synthetic lethality in those cancer cells. MTA-cooperative PRMT5 inhibitors such as BMS-986504/MRTX1719 and AMG 193 target the PRMT5-MTA complex, while inhibitors of the SAM synthetase methionine adenosyl transferase 2A (MAT2A), such as IDE397, deprive PRMT5 of its methyl donor SAM. In this review article, we summarize the mechanisms of action, preclinical data, and clinical data available thus far for these novel classes of oncology precision medicine and discuss potential future directions relevant to MTAP deletion as a promising synthetic lethal vulnerability for cancer therapy.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"6 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937774","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}
Radiotherapy plays a central role in cancer treatment, and the immunostimulatory effects of radiotherapy have been increasingly recognized. A better understanding of the mechanisms underlying post-radiation immune escape is needed to help overcome radioresistance. Here, we identified that irradiated tumor cells exploit the ANAPC5/GPAA1 axis to elevate surface expression of the "don't eat me" signal CD24, inducing phagocytosis resistance and immune evasion. Mechanistically, radiation inhibited the APC/C complex, reducing ANAPC5-mediated ubiquitination of GPAA1, a catalytic subunit of glycosylphosphatidylinositol (GPI) transamidase. The subsequent accumulation of GPAA1 facilitated GPI anchoring, thereby enhancing CD24 membrane localization. Accordingly, ablation of GPAA1 or CD24 significantly potentiated the local antitumor effects of radiotherapy across multiple preclinical models, dependent on T cells and macrophages. Notably, CD24 deficiency also stimulated abscopal effects, suppressing the growth of non-irradiated tumors. Overall, this study elucidates a mechanism of radiotherapy-mediated upregulation of the innate immune checkpoint CD24, offering perspectives on radiation-induced immune escape and presenting a strategy to improve radiotherapy efficacy.
{"title":"Radiation-Enhanced CD24 Membrane Trafficking via GPI Anchoring Mediates Anti-Tumor Immune Evasion.","authors":"Lingyi Kong,Minqi Zhou,Wenqian Yuan,Yijun Wang,Xixi Liu,Jiacheng Wang,Weidong Zhong,Qinyan Chen,Pengfei Li,Tingting Pu,Zishan Feng,Zhiyuan Zhou,Yue Deng,Wenwen Wei,Xiao Yang,Jingshu Meng,Yuhan Sheng,Chao Wan,Fang Huang,Kunyu Yang,Yajie Sun","doi":"10.1158/0008-5472.can-25-2616","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-2616","url":null,"abstract":"Radiotherapy plays a central role in cancer treatment, and the immunostimulatory effects of radiotherapy have been increasingly recognized. A better understanding of the mechanisms underlying post-radiation immune escape is needed to help overcome radioresistance. Here, we identified that irradiated tumor cells exploit the ANAPC5/GPAA1 axis to elevate surface expression of the \"don't eat me\" signal CD24, inducing phagocytosis resistance and immune evasion. Mechanistically, radiation inhibited the APC/C complex, reducing ANAPC5-mediated ubiquitination of GPAA1, a catalytic subunit of glycosylphosphatidylinositol (GPI) transamidase. The subsequent accumulation of GPAA1 facilitated GPI anchoring, thereby enhancing CD24 membrane localization. Accordingly, ablation of GPAA1 or CD24 significantly potentiated the local antitumor effects of radiotherapy across multiple preclinical models, dependent on T cells and macrophages. Notably, CD24 deficiency also stimulated abscopal effects, suppressing the growth of non-irradiated tumors. Overall, this study elucidates a mechanism of radiotherapy-mediated upregulation of the innate immune checkpoint CD24, offering perspectives on radiation-induced immune escape and presenting a strategy to improve radiotherapy efficacy.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"47 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937777","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}
Tumorigenesis is a multistep process requiring alterations in various gene expression programs. The transcription factor KLF5 is frequently genomically amplified and activated in multiple epithelial cancers, highlighting the need to define its role in the transformation of normal epithelium to cancer. Here, we used genetically engineered organoids to identify the function of KLF5 in tumorigenesis of multiple endodermal epithelial cancers. KLF5 activation drove a series of morphological and molecular events during the stepwise transformation of normal airway epithelium towards lung squamous cell carcinoma (LUSC) by remodeling protein biosynthesis and energy metabolism. Inhibition of ribosome biogenesis and oxidative phosphorylation attenuated the malignant progression of LUSC driven by KLF5. In summary, this study identified KLF5 as a crucial transcriptional modulator in LUSC oncogenesis and indicated that KLF5-activated LUSC may be therapeutically vulnerable to inhibition of ribosome biogenesis and oxidative phosphorylation.
{"title":"KLF5 Activation Promotes Malignant Transformation to Drive Development of Lung Squamous Cell Carcinoma.","authors":"Junwei Zeng,Qing Li,Jiaqi Zhang,Zhe Yu,Ning Jiang,Xinghua Cheng,Yin Li,Xinhua Lin,Xiaofang Tang","doi":"10.1158/0008-5472.can-25-2139","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-2139","url":null,"abstract":"Tumorigenesis is a multistep process requiring alterations in various gene expression programs. The transcription factor KLF5 is frequently genomically amplified and activated in multiple epithelial cancers, highlighting the need to define its role in the transformation of normal epithelium to cancer. Here, we used genetically engineered organoids to identify the function of KLF5 in tumorigenesis of multiple endodermal epithelial cancers. KLF5 activation drove a series of morphological and molecular events during the stepwise transformation of normal airway epithelium towards lung squamous cell carcinoma (LUSC) by remodeling protein biosynthesis and energy metabolism. Inhibition of ribosome biogenesis and oxidative phosphorylation attenuated the malignant progression of LUSC driven by KLF5. In summary, this study identified KLF5 as a crucial transcriptional modulator in LUSC oncogenesis and indicated that KLF5-activated LUSC may be therapeutically vulnerable to inhibition of ribosome biogenesis and oxidative phosphorylation.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"46 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937776","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 : 2026-01-09DOI: 10.1158/0008-5472.can-25-1217
Joseph L Sottnik,Madeleine T Shackleford,Camryn S Nesiba,Amanda L Richer,Zoe Fleischmann,Jordan M Swartz,Carmen E Rowland,Maggie Musick,Rui Fu,Logan R Myler,Patricia L Opresko,Sanjana Mehrotra,Ethan S Sokol,Jay R Hesselberth,Jennifer R Diamond,Matthew J Sikora
Invasive lobular carcinoma of the breast (ILC) is typically estrogen receptor α (ER)-positive and presents with biomarkers of anti-estrogen sensitive disease. Unfortunately, patients with ILC face particularly poor long-term outcomes with high recurrence risk, suggesting a divergent endocrine response and ER function in ILC compared to other breast cancers. ER is co-regulated by the DNA repair protein MDC1 specifically in ILC cells, driving distinct ER activity. Here, we profiled the MDC1 interactome to examine how MDC1 regulates ER activity and DNA repair function in ILC. MDC1-associated proteins in ILC cells mirrored a "BRCA-like" state lacking key homologous recombination (HR) proteins, consistent with HR dysfunction but distinct from classic "BRCAness". Single-cell transcriptome and DNA repair activity analyses, along with DNA repair signaling and functional data, substantiated dysfunctional induction and execution of HR in ILC cells. In parallel, ILC tumor data were consistent with a form of HR dysfunction distinct from overt HR deficiency, lacking BRCA-like genomic scarring but showing elevated signatures of PARP inhibitor sensitivity. Treatment with the PARP inhibitor talazoparib produced a durable growth suppression both in vitro and in multiple ILC xenografts in vivo. Together, these findings reveal that ILC-specific ER:MDC1 activity comes at the cost of DNA repair dysfunction, which may be therapeutically targetable.
{"title":"Altered MDC1 Interactions and Dysfunctional DNA Repair in Lobular Breast Cancer Confers Sensitivity to PARP Inhibition.","authors":"Joseph L Sottnik,Madeleine T Shackleford,Camryn S Nesiba,Amanda L Richer,Zoe Fleischmann,Jordan M Swartz,Carmen E Rowland,Maggie Musick,Rui Fu,Logan R Myler,Patricia L Opresko,Sanjana Mehrotra,Ethan S Sokol,Jay R Hesselberth,Jennifer R Diamond,Matthew J Sikora","doi":"10.1158/0008-5472.can-25-1217","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-1217","url":null,"abstract":"Invasive lobular carcinoma of the breast (ILC) is typically estrogen receptor α (ER)-positive and presents with biomarkers of anti-estrogen sensitive disease. Unfortunately, patients with ILC face particularly poor long-term outcomes with high recurrence risk, suggesting a divergent endocrine response and ER function in ILC compared to other breast cancers. ER is co-regulated by the DNA repair protein MDC1 specifically in ILC cells, driving distinct ER activity. Here, we profiled the MDC1 interactome to examine how MDC1 regulates ER activity and DNA repair function in ILC. MDC1-associated proteins in ILC cells mirrored a \"BRCA-like\" state lacking key homologous recombination (HR) proteins, consistent with HR dysfunction but distinct from classic \"BRCAness\". Single-cell transcriptome and DNA repair activity analyses, along with DNA repair signaling and functional data, substantiated dysfunctional induction and execution of HR in ILC cells. In parallel, ILC tumor data were consistent with a form of HR dysfunction distinct from overt HR deficiency, lacking BRCA-like genomic scarring but showing elevated signatures of PARP inhibitor sensitivity. Treatment with the PARP inhibitor talazoparib produced a durable growth suppression both in vitro and in multiple ILC xenografts in vivo. Together, these findings reveal that ILC-specific ER:MDC1 activity comes at the cost of DNA repair dysfunction, which may be therapeutically targetable.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"8 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937775","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: 10.1158/0008-5472.can-24-3891
Sarah K Herzog,Jessica H Stevens,Guowei Gu,Sandra L Grimm,Kloma Cardoza,Autumn G M Hawkins,Hangqing Lin,Daniela Ramos,Amanda R Beyer,David G Edwards,Derek Dustin,Harry J Yang,Nicole Liang,Ashfia F Khan,Tasneem Bawa-Khalfe,Daniel J McGrail,Shiaw-Yih Lin,Cristian Coarfa,Suzanne A W Fuqua
ESR1 mutations are the leading cause of endocrine therapy resistance and progression in ER-positive metastatic breast cancer. ESR1 mutations are detected in ~50% of metastatic breast cancer patients, and identification of effective targeted therapeutics are critically needed. Here, we identified enrichment of dysregulated replication stress and DNA damage responses in multiple ESR1 mutant models. Targeting the replication stress response utilizing checkpoint inhibition in combination with PARP inhibition synergistically suppressed growth, induced cell cycle arrest, and attenuated DNA replication. PARP inhibition blocked metastatic dissemination in vivo and reduced both PARP1 and ER-regulated protein expression. PARP trapping by olaparib treatment with or without endocrine therapy resulted in a significant increase of co-localized DNA-bound PARP1 and ER protein in ESR1 mutant cells, indicating ER-PARP1 co-regulation in ESR1 mutant breast cancer. Long-term treatment with endocrine therapy plus the CDK4/6 inhibitor abemaciclib led to the emergence of a Y537S ESR1 mutation in a cell line, which exhibited dysregulation of replication stress response, enhanced DNA damage response, and synergistic responses to inhibitors of these pathways. PARP inhibition also synergized with clinically relevant endocrine therapy in ESR1 mutant models, reducing tumor growth both ex vivo and in vivo. Together, these results identify replication stress and DNA damage responses as key dysregulated pathways in ESR1 mutant breast cancer with significant clinical potential for PARP inhibition in this metastatic breast cancer subset.
{"title":"Defective DNA Damage Response is a Targetable Therapeutic Vulnerability in ESR1 Mutant Breast Cancer.","authors":"Sarah K Herzog,Jessica H Stevens,Guowei Gu,Sandra L Grimm,Kloma Cardoza,Autumn G M Hawkins,Hangqing Lin,Daniela Ramos,Amanda R Beyer,David G Edwards,Derek Dustin,Harry J Yang,Nicole Liang,Ashfia F Khan,Tasneem Bawa-Khalfe,Daniel J McGrail,Shiaw-Yih Lin,Cristian Coarfa,Suzanne A W Fuqua","doi":"10.1158/0008-5472.can-24-3891","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3891","url":null,"abstract":"ESR1 mutations are the leading cause of endocrine therapy resistance and progression in ER-positive metastatic breast cancer. ESR1 mutations are detected in ~50% of metastatic breast cancer patients, and identification of effective targeted therapeutics are critically needed. Here, we identified enrichment of dysregulated replication stress and DNA damage responses in multiple ESR1 mutant models. Targeting the replication stress response utilizing checkpoint inhibition in combination with PARP inhibition synergistically suppressed growth, induced cell cycle arrest, and attenuated DNA replication. PARP inhibition blocked metastatic dissemination in vivo and reduced both PARP1 and ER-regulated protein expression. PARP trapping by olaparib treatment with or without endocrine therapy resulted in a significant increase of co-localized DNA-bound PARP1 and ER protein in ESR1 mutant cells, indicating ER-PARP1 co-regulation in ESR1 mutant breast cancer. Long-term treatment with endocrine therapy plus the CDK4/6 inhibitor abemaciclib led to the emergence of a Y537S ESR1 mutation in a cell line, which exhibited dysregulation of replication stress response, enhanced DNA damage response, and synergistic responses to inhibitors of these pathways. PARP inhibition also synergized with clinically relevant endocrine therapy in ESR1 mutant models, reducing tumor growth both ex vivo and in vivo. Together, these results identify replication stress and DNA damage responses as key dysregulated pathways in ESR1 mutant breast cancer with significant clinical potential for PARP inhibition in this metastatic breast cancer subset.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"82 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907713","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: 10.1158/0008-5472.can-24-3113
Naiara Perurena, Marina Watanabe, Amy E. Schade, William Brown, Elizabeth Y. Luo, Alycia Gardner, Alexandra Indeglia, Akiko Yoshinaga, Rhea Sahu, Yoona Yang, Simon R.V. Knott, Karen Cichowski
Human epidermal growth factor receptor 2 positive (HER2+) tumors account for 20% of breast cancers. While a variety of HER2-targeted therapies have been developed, tumors can exhibit de novo or acquired resistance, and metastatic disease remains incurable. Here, we showed that EZH2 inhibitors shift the epigenetic state of HER2+ tumors, dramatically enhancing baseline responses to HER2 kinase inhibitors and re-sensitizing drug-resistant tumors in vitro and in vivo. Specifically, EZH2 silenced the pro-apoptotic gene BMF by catalyzing H3K27 trimethylation (H3K27me3) at regulatory sequences. EZH2 inhibitors promoted the loss of H3K27me3, but this stimulated the binding of repressive YAP/TEAD complexes at the BMF locus, which still restricted expression. However, in the presence of EZH2 inhibitors, HER2 kinase inhibitors triggered the dissociation of repressive YAP/TEAD complexes, potently upregulated BMF, and killed resistant cells. Accordingly, EZH2 inhibitors cooperated with genetic or pharmacological inhibition of YAP/TEAD, which similarly induced BMF expression and apoptosis. Together, these findings show how EZH2 and YAP/TEAD coordinately insulate the BMF locus and demonstrate that EZH2 inhibitors can be used to reprogram HER2+ tumors, resulting in a dramatic sensitization to HER2 kinase inhibitors and enhanced killing of residual disease.
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