Pub Date : 2026-01-20DOI: 10.1158/1538-7445.prostateca26-b032
Juan M. Jiménez-Vacas, Jonathan Welti, Denisa Bogdan, Ines Figueiredo, Bora Gurel, Wanting Zeng, Tomas Goldsmith, Souvik Das, Joe Taylor, Nicholas Waldron, Claudia Bertan, Suzanne Carreira, Wei Yuan, Paul Workman, Steven P. Balk, Johann de Bono, Adam Sharp
Background: Despite recent therapeutic advances, advanced prostate cancer (PCa) remains lethal as tumors develop resistance to current treatments. Novel and more effective therapeutic strategies to induce cell death in these tumors are urgently needed. Our group recently reported that NXP800, a drug in clinical development, drives unfolded protein response (UPR) and targets AR and E2F, decreasing the growth of castration-resistant PCa (CRPC) models in vitro and in vivo. BH3 mimetics are small molecules that inhibit antiapoptotic BCL-2 family proteins, thereby promoting apoptosis, and have shown particular promise in hematological malignancies. However, their efficacy in CRPC has been limited, likely due to functional redundancies among antiapoptotic proteins such as MCL1, BCLXL, and BCL2. Objective: We investigated the potential of combining NXP800 with BH3 mimetics targeting MCL1 (S63845) or BCLXL (A-1331852) to drive cell death by inducing the intrinsic apoptosis pathway in CRPC models. Methods: Cell viability and caspase 3/7 activity were assessed by luminescence assays, while additional apoptosis markers were evaluated by western blot following treatment with NXP800, S63845, and A-1331852, as single agents or in combination. To identify key mediators of the synergistic effects, an siRNA screen targeting BH3-only proteins was performed in CRPC cells before treatment with the single agents or their combination. To assess the molecular consequences of NXP800 treatment in vivo, RNA-seq was performed on tumors from CRPC-bearing mice treated with NXP800 (35 mg/kg daily for 5 days), with particular focus on genes involved in the intrinsic apoptosis pathway. Results: NXP800 synergized with MCL1 and BCLXL inhibitors in CRPC cells, inducing apoptosis as evidenced by caspase 3/7 activation and PARP cleavage. Co-silencing of the mitochondrial pore–forming proteins BAX and BAK, as well as treatment with the pan-caspase inhibitor Q-VD-OPh, prevented cell death induced by NXP800 in combination with BH3 mimetics, indicating that the effect is caspase-dependent and involves activation of the intrinsic apoptosis pathway. Blocking NXP800-induced eIF2α phosphorylation using ISRIB abolished the synergistic effect observed with BH3 mimetics. Thapsigargin, which induces the unfolded protein response via SERCA inhibition, recapitulated the synergy and triggered apoptosis in combination with BH3 mimetics. RNA-seq analysis of LNCaP95 xenograft tumors treated with NXP800 revealed induction of specific BH3-only proteins whose silencing (in vitro) prevented caspase 3/7 activation and abolished the synergistic cell death observed with NXP800 in combination with MCL1 or BCLXL inhibition. Conclusion: NXP800 sensitizes CRPC cells to BH3 mimetics by inducing UPR and dysregulating BH3-only proteins. These findings highlight the potential of combining UPR-inducing agents with BH3 mimetics as a therapeutic strategy in CRPC. Citation Format: Juan M. Jiménez-Vacas, Jonathan Welti,
背景：尽管最近的治疗取得了进展，晚期前列腺癌（PCa）仍然是致命的，因为肿瘤对目前的治疗产生了耐药性。迫切需要新的和更有效的治疗策略来诱导这些肿瘤的细胞死亡。我们的团队最近报道了一种临床开发的药物NXP800，它可以驱动未折叠蛋白反应（UPR），靶向AR和E2F，在体外和体内降低去势抵抗性PCa （CRPC）模型的生长。BH3模拟物是抑制抗凋亡BCL-2家族蛋白的小分子，从而促进细胞凋亡，并在血液恶性肿瘤中显示出特别的希望。然而，它们在CRPC中的疗效有限，可能是由于抗凋亡蛋白如MCL1、BCLXL和BCL2之间的功能冗余。目的：探讨NXP800联合靶向MCL1 （S63845）或BCLXL （A-1331852）的BH3模拟物在CRPC模型中通过诱导内在凋亡途径驱动细胞死亡的潜力。方法：采用荧光法检测细胞活力和caspase 3/7活性，western blot检测NXP800、S63845和A-1331852单独或联合作用后细胞凋亡标志物。为了确定协同作用的关键介质，在使用单一药物或联合药物治疗前，在CRPC细胞中进行了针对BH3-only蛋白的siRNA筛选。为了评估NXP800在体内的分子效应，研究人员对携带crpc的小鼠的肿瘤进行了rna测序（每天35 mg/kg，持续5天），特别关注与内在凋亡途径相关的基因。结果：NXP800在CRPC细胞中与MCL1和BCLXL抑制剂协同作用，通过caspase 3/7活化和PARP切割诱导细胞凋亡。共沉默线粒体孔形成蛋白BAX和BAK，以及用泛caspase抑制剂Q-VD-OPh处理，可以防止NXP800联合BH3模拟物诱导的细胞死亡，表明这种作用依赖于caspase，涉及激活内在凋亡途径。使用ISRIB阻断nxp800诱导的eIF2α磷酸化，可以消除BH3模拟物的协同效应。Thapsigargin通过抑制SERCA诱导未折叠蛋白反应，再现了协同作用并与BH3模拟物联合引发细胞凋亡。NXP800对LNCaP95异种移植肿瘤的RNA-seq分析显示，特异性BH3-only蛋白的诱导，其沉默（体外）阻止了caspase 3/7的激活，并消除了NXP800与MCL1或BCLXL联合抑制时观察到的协同细胞死亡。结论：NXP800通过诱导UPR和BH3-only蛋白失调使CRPC细胞对BH3模拟物增敏。这些发现强调了将upr诱导剂与BH3模拟物结合作为CRPC治疗策略的潜力。引文格式：Juan M. jimsamunez - vacas, Jonathan Welti, Denisa Bogdan, Ines Figueiredo, Bora Gurel, wanging Zeng, Tomas Goldsmith, Souvik Das, Joe Taylor, Nicholas Waldron, Claudia Bertan, Suzanne Carreira, Wei Yuan, Paul Workman, Steven P. Balk, Johann de Bono, Adam Sharp。未折叠蛋白反应的诱导揭示了晚期前列腺癌细胞对BH3模拟物的脆弱性[摘要]。摘自：美国癌症研究协会癌症研究特别会议论文集：前列腺癌研究和治疗的创新；2026年1月20日至22日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86（增刊）：B032。
{"title":"Abstract B032: Induction of the unfolded protein response unveils a vulnerability of advanced prostate cancer cells to BH3 mimetics","authors":"Juan M. Jiménez-Vacas, Jonathan Welti, Denisa Bogdan, Ines Figueiredo, Bora Gurel, Wanting Zeng, Tomas Goldsmith, Souvik Das, Joe Taylor, Nicholas Waldron, Claudia Bertan, Suzanne Carreira, Wei Yuan, Paul Workman, Steven P. Balk, Johann de Bono, Adam Sharp","doi":"10.1158/1538-7445.prostateca26-b032","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b032","url":null,"abstract":"Background: Despite recent therapeutic advances, advanced prostate cancer (PCa) remains lethal as tumors develop resistance to current treatments. Novel and more effective therapeutic strategies to induce cell death in these tumors are urgently needed. Our group recently reported that NXP800, a drug in clinical development, drives unfolded protein response (UPR) and targets AR and E2F, decreasing the growth of castration-resistant PCa (CRPC) models in vitro and in vivo. BH3 mimetics are small molecules that inhibit antiapoptotic BCL-2 family proteins, thereby promoting apoptosis, and have shown particular promise in hematological malignancies. However, their efficacy in CRPC has been limited, likely due to functional redundancies among antiapoptotic proteins such as MCL1, BCLXL, and BCL2. Objective: We investigated the potential of combining NXP800 with BH3 mimetics targeting MCL1 (S63845) or BCLXL (A-1331852) to drive cell death by inducing the intrinsic apoptosis pathway in CRPC models. Methods: Cell viability and caspase 3/7 activity were assessed by luminescence assays, while additional apoptosis markers were evaluated by western blot following treatment with NXP800, S63845, and A-1331852, as single agents or in combination. To identify key mediators of the synergistic effects, an siRNA screen targeting BH3-only proteins was performed in CRPC cells before treatment with the single agents or their combination. To assess the molecular consequences of NXP800 treatment in vivo, RNA-seq was performed on tumors from CRPC-bearing mice treated with NXP800 (35 mg/kg daily for 5 days), with particular focus on genes involved in the intrinsic apoptosis pathway. Results: NXP800 synergized with MCL1 and BCLXL inhibitors in CRPC cells, inducing apoptosis as evidenced by caspase 3/7 activation and PARP cleavage. Co-silencing of the mitochondrial pore–forming proteins BAX and BAK, as well as treatment with the pan-caspase inhibitor Q-VD-OPh, prevented cell death induced by NXP800 in combination with BH3 mimetics, indicating that the effect is caspase-dependent and involves activation of the intrinsic apoptosis pathway. Blocking NXP800-induced eIF2α phosphorylation using ISRIB abolished the synergistic effect observed with BH3 mimetics. Thapsigargin, which induces the unfolded protein response via SERCA inhibition, recapitulated the synergy and triggered apoptosis in combination with BH3 mimetics. RNA-seq analysis of LNCaP95 xenograft tumors treated with NXP800 revealed induction of specific BH3-only proteins whose silencing (in vitro) prevented caspase 3/7 activation and abolished the synergistic cell death observed with NXP800 in combination with MCL1 or BCLXL inhibition. Conclusion: NXP800 sensitizes CRPC cells to BH3 mimetics by inducing UPR and dysregulating BH3-only proteins. These findings highlight the potential of combining UPR-inducing agents with BH3 mimetics as a therapeutic strategy in CRPC. Citation Format: Juan M. Jiménez-Vacas, Jonathan Welti,","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"45 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006159","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 : 2026-01-20DOI: 10.1158/1538-7445.prostateca26-b028
Saskia Elena. Haarmann, Martin Eilers, Steffi Herold
The androgen receptor (AR) is a key driver of prostate cancer progression, making androgen deprivation therapy and AR signaling inhibitors the standard of care therapies for treating prostate cancer. Although these treatments are effective initially, they often lead to the development of resistance, limiting their long-term efficacy. This acquired resistance is frequently linked to the MYC oncogene family, which, together with reduced AR signaling, is associated with poor clinical prognosis. Among the resistant phenotypes, treatment-induced neuroendocrine prostate cancer (tNEPC) is a particularly aggressive AR-independent subtype characterized by loss of AR signaling and epigenetic reprogramming. These molecular changes promote cell lineage plasticity, creating a permissive environment for MYCN activation, which further drives tumor progression and neuroendocrine differentiation. In summary, MYC proteins pose a major biological challenge, but also offer opportunities to develop new therapeutic approaches. To address these, we generated LNCaP-derived prostate cancer cell lines that constitutively express c-MYC or MYCN. Their sustained proliferation under enzalutamide treatment confirmed the development of a resistant phenotype. In addition, RNA sequencing of MYCN-overexpressing cells revealed transcriptional reprogramming, including the activation of neural lineage markers and epithelial-mesenchymal transition programs consistent with a neuroendocrine-like phenotype. To identify dependency factors, we performed a genome-wide shRNA screen to uncover genes whose knockdown selectively impaired growth of LNCaP cells expressing c-MYC or MYCN under enzalutamide. In c-MYC-expressing cells approximately 80 significantly downregulated genes were identified, many of which had previously been associated with therapeutic resistance. Interestingly, a substantial proportion of these factors were also significantly enriched in RNA processing and metabolic pathways. Both c-MYC and MYCN bind directly to DNA as well as RNA, and recent studies have revealed that MYC proteins play distinct mechanistic roles in transcriptional regulation and RNA metabolism. The newly described RNA-related functions of MYC highlight the importance of RNA regulatory mechanisms as key drivers of MYC-dependent oncogenesis in prostate cancer. Approximately 20 genes were significantly downregulated in MYCN-expressing cells, most of which are involved in RNA splicing. This is an intriguing observation given that MYCN is a well-characterized transcription factor that orchestrates transcriptional reprogramming. The data suggest that MYCN can influence oncogenic processes by modulating RNA splicing mechanisms, revealing an additional level of regulatory complexity in tNEPC. Ongoing validation and integrative analyses, including bulk mRNA-sequencing of patient data, aim to define the roles of these genes, delineate pathways, and identify novel therapeutic targets to overcome MYC-mediated and AR-
{"title":"Abstract B028: Global shRNA screen to identify factors that are involved in MYC/MYCN-dependent growth of prostate cancer","authors":"Saskia Elena. Haarmann, Martin Eilers, Steffi Herold","doi":"10.1158/1538-7445.prostateca26-b028","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b028","url":null,"abstract":"The androgen receptor (AR) is a key driver of prostate cancer progression, making androgen deprivation therapy and AR signaling inhibitors the standard of care therapies for treating prostate cancer. Although these treatments are effective initially, they often lead to the development of resistance, limiting their long-term efficacy. This acquired resistance is frequently linked to the MYC oncogene family, which, together with reduced AR signaling, is associated with poor clinical prognosis. Among the resistant phenotypes, treatment-induced neuroendocrine prostate cancer (tNEPC) is a particularly aggressive AR-independent subtype characterized by loss of AR signaling and epigenetic reprogramming. These molecular changes promote cell lineage plasticity, creating a permissive environment for MYCN activation, which further drives tumor progression and neuroendocrine differentiation. In summary, MYC proteins pose a major biological challenge, but also offer opportunities to develop new therapeutic approaches. To address these, we generated LNCaP-derived prostate cancer cell lines that constitutively express c-MYC or MYCN. Their sustained proliferation under enzalutamide treatment confirmed the development of a resistant phenotype. In addition, RNA sequencing of MYCN-overexpressing cells revealed transcriptional reprogramming, including the activation of neural lineage markers and epithelial-mesenchymal transition programs consistent with a neuroendocrine-like phenotype. To identify dependency factors, we performed a genome-wide shRNA screen to uncover genes whose knockdown selectively impaired growth of LNCaP cells expressing c-MYC or MYCN under enzalutamide. In c-MYC-expressing cells approximately 80 significantly downregulated genes were identified, many of which had previously been associated with therapeutic resistance. Interestingly, a substantial proportion of these factors were also significantly enriched in RNA processing and metabolic pathways. Both c-MYC and MYCN bind directly to DNA as well as RNA, and recent studies have revealed that MYC proteins play distinct mechanistic roles in transcriptional regulation and RNA metabolism. The newly described RNA-related functions of MYC highlight the importance of RNA regulatory mechanisms as key drivers of MYC-dependent oncogenesis in prostate cancer. Approximately 20 genes were significantly downregulated in MYCN-expressing cells, most of which are involved in RNA splicing. This is an intriguing observation given that MYCN is a well-characterized transcription factor that orchestrates transcriptional reprogramming. The data suggest that MYCN can influence oncogenic processes by modulating RNA splicing mechanisms, revealing an additional level of regulatory complexity in tNEPC. Ongoing validation and integrative analyses, including bulk mRNA-sequencing of patient data, aim to define the roles of these genes, delineate pathways, and identify novel therapeutic targets to overcome MYC-mediated and AR-","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"3 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006189","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 : 2026-01-20DOI: 10.1158/1538-7445.prostateca26-a008
Ruhollah Moussavi-Baygi, Matthew Ryan, Woogwang Sim, Samuel Hoelscher, Valbona Luga, Arun Chandrakumar, Lore Hoes, Junghwa Cha, Young Sun Lee, Katelyn Herm, Ben Doron, Danika Bakke, C.K. Cornelia Ding, Bradley Stohr, Peng Jin, Tejasveeta Nadkarni, Xiangyi Fang, Melita Haryono, An Nguyen, Wouter Karthaus, Charles Sawyers, Felix Feng, Hani Goodarzi, Rohit Bose
Rising incidence of early-onset prostate and other solid tumors underscores the need for experimental systems that model how normal tissues traverse premalignant states, acquire mutations, and become therapy-responsive malignancies under authentic immune and stromal pressures. A major barrier has been the lack of tractable in vivo platforms that enable genome-wide discovery while preserving continuous tumor evolution without catastrophic chromosomal instability. To address this, the Bose Lab developed Stochastically Emergent Tumors (SETs), an organoid-derived in vivo evolution engine that redefines discovery for early-onset and understudied patient groups. In this system, mismatch-repair deficiency is induced in non-malignant human organoids, which are passaged to accumulate stochastic point mutations and transplanted into mice to permit malignancy to emerge under physiologic selection. SETs evolve primarily through high-resolution point mutations rather than broad copy-number changes, yielding bioinformatically tractable clonal dynamics ideally suited for whole-genome driver discovery and machine learning. Compared with conventional xenografts, SETs display greater intertumoral heterogeneity and reproducible recovery of sensitizing and resistance alleles under therapeutic pressure. As proof of principle in prostate cancer, endocrine therapy applied to SET pools recovered known determinants of androgen-pathway sensitivity and uncovered new drivers. Loss of ZFHX3, typically obscured within a multigene suppressor locus in bulk cohorts, promoted luminal histology and sensitized tumors to androgen-receptor inhibition in vivo, whereas KMT2D or CIC alterations mediated resistance. Consistent with model predictions, ZFHX3 loss in patients correlated with significantly improved survival, a finding comparable in magnitude to the most favorable molecular subtypes of advanced prostate cancer. SETs also quantify evolutionary thresholds: in a Pten-null background, approximately 900 coding mutations accumulated over 208 days were sufficient for malignant transformation in half of grafts. This defines a measurable axis linking mutation burden, genotype, and tumor incidence. Because SETs generate neoantigen-rich point-mutation landscapes, they can be extended to immunocompetent hosts to study tumor–immune coevolution, early T-cell surveillance, macrophage-mediated immune exclusion, and myeloid checkpoints that enable immune escape. In summary, SETs provide a scalable, evolution-aware platform that connects mutational dynamics to therapeutic vulnerability, enabling identification of lineage- and ancestry-associated drivers, immunopreventive targets, and biomarkers of early-onset prostate cancer. Citation Format: Ruhollah Moussavi-Baygi, Matthew Ryan, Woogwang Sim, Samuel Hoelscher, Valbona Luga, Arun Chandrakumar, Lore Hoes, Junghwa Cha, Young Sun Lee, Katelyn Herm, Ben Doron, Danika Bakke, C.K. Cornelia Ding, Bradley Stohr, Peng Jin, Tejasveeta Nadkarni, Xiangyi
早发性前列腺瘤和其他实体瘤的发病率不断上升，这强调了对实验系统的需求，这些实验系统可以模拟正常组织如何在真实的免疫和基质压力下穿越癌前状态、获得突变并成为治疗反应性恶性肿瘤。一个主要的障碍是缺乏可处理的体内平台，使全基因组的发现，同时保持连续的肿瘤进化没有灾难性的染色体不稳定性。为了解决这个问题，Bose实验室开发了随机发生肿瘤（SETs），这是一种源自类器官的体内进化引擎，重新定义了早发和未充分研究的患者群体的发现。在这个系统中，在非恶性的人类类器官中诱导错配修复缺陷，通过传代积累随机点突变并移植到小鼠体内，使恶性肿瘤在生理选择下出现。set的进化主要是通过高分辨率的点突变，而不是广泛的拷贝数变化，产生生物信息上可处理的克隆动力学，非常适合全基因组驱动发现和机器学习。与传统的异种移植物相比，set在治疗压力下表现出更大的肿瘤间异质性和可重复的致敏和抗性等位基因恢复。作为前列腺癌的原理证明，应用于SET池的内分泌治疗恢复了雄激素通路敏感性的已知决定因素，并发现了新的驱动因素。ZFHX3的缺失，通常隐藏在一个多基因抑制位点中，在体内促进了腔内组织学和使肿瘤对雄激素受体抑制敏感，而KMT2D或CIC的改变介导了耐药性。与模型预测一致，患者的ZFHX3缺失与生存率显著提高相关，这一发现与晚期前列腺癌最有利的分子亚型相当。set还量化了进化阈值：在pten缺失的背景下，在208天内积累的大约900个编码突变足以使一半的移植物发生恶性转化。这定义了一个可测量的轴，将突变负担、基因型和肿瘤发生率联系起来。由于set产生富含新抗原的点突变景观，它们可以扩展到免疫能力强的宿主，以研究肿瘤免疫协同进化、早期t细胞监视、巨噬细胞介导的免疫排斥和使免疫逃逸的骨髓检查点。总之，set提供了一个可扩展的、进化感知的平台，将突变动力学与治疗易感性联系起来，能够识别谱系和祖先相关的驱动因素、免疫预防靶点和早发性前列腺癌的生物标志物。引用格式：Ruhollah Moussavi-Baygi， Matthew Ryan, Woogwang Sim, Samuel Hoelscher, Valbona Luga, Arun Chandrakumar, Lore Hoes, junhwa Cha, Young Sun Lee, Katelyn Herm, Ben Doron, Danika Bakke， C.K. Cornelia Ding, Bradley Stohr, Peng Jin, Tejasveeta Nadkarni, Xiangyi Fang, Melita Haryono, An Nguyen, Wouter Karthaus, Charles Sawyers, Felix Feng, Hani Goodarzi, Rohit Bose。随机突发性肿瘤（set）重建前列腺进化揭示了体内治疗脆弱性[摘要]。摘自：美国癌症研究协会癌症研究特别会议论文集：前列腺癌研究和治疗的创新；2026年1月20日至22日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86（增刊）：no A008。
{"title":"Abstract A008: Reconstructing prostate evolution with Stochastically Emergent Tumors (SETs) reveals in vivo therapeutic vulnerabilities","authors":"Ruhollah Moussavi-Baygi, Matthew Ryan, Woogwang Sim, Samuel Hoelscher, Valbona Luga, Arun Chandrakumar, Lore Hoes, Junghwa Cha, Young Sun Lee, Katelyn Herm, Ben Doron, Danika Bakke, C.K. Cornelia Ding, Bradley Stohr, Peng Jin, Tejasveeta Nadkarni, Xiangyi Fang, Melita Haryono, An Nguyen, Wouter Karthaus, Charles Sawyers, Felix Feng, Hani Goodarzi, Rohit Bose","doi":"10.1158/1538-7445.prostateca26-a008","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-a008","url":null,"abstract":"Rising incidence of early-onset prostate and other solid tumors underscores the need for experimental systems that model how normal tissues traverse premalignant states, acquire mutations, and become therapy-responsive malignancies under authentic immune and stromal pressures. A major barrier has been the lack of tractable in vivo platforms that enable genome-wide discovery while preserving continuous tumor evolution without catastrophic chromosomal instability. To address this, the Bose Lab developed Stochastically Emergent Tumors (SETs), an organoid-derived in vivo evolution engine that redefines discovery for early-onset and understudied patient groups. In this system, mismatch-repair deficiency is induced in non-malignant human organoids, which are passaged to accumulate stochastic point mutations and transplanted into mice to permit malignancy to emerge under physiologic selection. SETs evolve primarily through high-resolution point mutations rather than broad copy-number changes, yielding bioinformatically tractable clonal dynamics ideally suited for whole-genome driver discovery and machine learning. Compared with conventional xenografts, SETs display greater intertumoral heterogeneity and reproducible recovery of sensitizing and resistance alleles under therapeutic pressure. As proof of principle in prostate cancer, endocrine therapy applied to SET pools recovered known determinants of androgen-pathway sensitivity and uncovered new drivers. Loss of ZFHX3, typically obscured within a multigene suppressor locus in bulk cohorts, promoted luminal histology and sensitized tumors to androgen-receptor inhibition in vivo, whereas KMT2D or CIC alterations mediated resistance. Consistent with model predictions, ZFHX3 loss in patients correlated with significantly improved survival, a finding comparable in magnitude to the most favorable molecular subtypes of advanced prostate cancer. SETs also quantify evolutionary thresholds: in a Pten-null background, approximately 900 coding mutations accumulated over 208 days were sufficient for malignant transformation in half of grafts. This defines a measurable axis linking mutation burden, genotype, and tumor incidence. Because SETs generate neoantigen-rich point-mutation landscapes, they can be extended to immunocompetent hosts to study tumor–immune coevolution, early T-cell surveillance, macrophage-mediated immune exclusion, and myeloid checkpoints that enable immune escape. In summary, SETs provide a scalable, evolution-aware platform that connects mutational dynamics to therapeutic vulnerability, enabling identification of lineage- and ancestry-associated drivers, immunopreventive targets, and biomarkers of early-onset prostate cancer. Citation Format: Ruhollah Moussavi-Baygi, Matthew Ryan, Woogwang Sim, Samuel Hoelscher, Valbona Luga, Arun Chandrakumar, Lore Hoes, Junghwa Cha, Young Sun Lee, Katelyn Herm, Ben Doron, Danika Bakke, C.K. Cornelia Ding, Bradley Stohr, Peng Jin, Tejasveeta Nadkarni, Xiangyi","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"63 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006221","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 : 2026-01-20DOI: 10.1158/1538-7445.prostateca26-b049
Niamh Murphy, Emma Allott, Declan McKenna, Suneil Jain, Ross Murphy
Background: Prostate cancer is among the most common causes of cancer-related mortality for males globally. A major challenge lies in distinguishing indolent from potentially fatal disease at the time of diagnosis. Hypertension is associated with an increased risk of developing prostate cancer. However, evidence suggests that antihypertensive medication usage could be associated with better outcomes for patients with prostate cancer. Despite this, the underlying tumour biology of hypertension in patients with prostate cancer has not been characterised. Materials and Methods: We analysed 466 patients with intermediate-to-high risk prostate cancer receiving radiotherapy and androgen deprivation therapy, of whom 248 patients had tumour gene expression profiling. High-risk prostate cancer was defined as Cambridge Prognostic Group (CPG) 4 or 5, or having a Gleason score ≥ 8. Multivariate survival analysis, including age and initial prostate specific antigen levels as covariates, was used to determine the relationship between hypertension status at diagnosis with prostate cancer, prostate cancer risk groups, and metastatic disease. Differential gene expression was performed for hypertension status at diagnosis with prostate cancer and metastatic disease. Immune and stromal cell estimation scores, and Hallmark gene sets, were inferred using patient tumour gene expression profiles. Results and Discussion: Hypertension status at diagnosis with prostate cancer was not associated with metastatic disease. When classifying by Gleason score risk, hypertension had significantly better outcomes for metastatic disease in high-risk patients (HR = 0.43, p-value = 0.009), but not in low- and intermediate-risk patients (HR = 1.86, p-value = 0.18; p-interaction = 0.022). However, when classifying by CPG risk, hypertension was not associated with metastatic disease in high-risk patients or low- and intermediate-risk patients. 142 genes were differentially expressed for hypertension status at diagnosis of prostate cancer (p-value < 0.01), of which 4 were also differentially expressed in relation to metastatic disease (p-value < 0.01). Immune and stromal cell type estimation scores and Hallmark gene sets were not differentially expressed for hypertension status at diagnosis of prostate cancer. Conclusion: Hypertension was protective of metastatic disease in patients diagnosed with high-risk prostate cancer, but not in patients diagnosed with low- and intermediate-risk prostate cancer. Our ongoing analysis will aim to validate these findings in separate independent prostate cancer cohorts and to assess whether the observed associations are influenced by antihypertensive medication use prior to diagnosis. Using hypertension as a surrogate for antihypertensive medication usage, our analysis could potentially suggest antihypertensive medication as repurposed, preventative therapeutics for high-risk prostate cancer. Citation Format: Niamh Murphy, Emma Allott, De
{"title":"Abstract B049: Hypertension is significantly associated with better outcomes in high-risk patients with prostate cancer","authors":"Niamh Murphy, Emma Allott, Declan McKenna, Suneil Jain, Ross Murphy","doi":"10.1158/1538-7445.prostateca26-b049","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b049","url":null,"abstract":"Background: Prostate cancer is among the most common causes of cancer-related mortality for males globally. A major challenge lies in distinguishing indolent from potentially fatal disease at the time of diagnosis. Hypertension is associated with an increased risk of developing prostate cancer. However, evidence suggests that antihypertensive medication usage could be associated with better outcomes for patients with prostate cancer. Despite this, the underlying tumour biology of hypertension in patients with prostate cancer has not been characterised. Materials and Methods: We analysed 466 patients with intermediate-to-high risk prostate cancer receiving radiotherapy and androgen deprivation therapy, of whom 248 patients had tumour gene expression profiling. High-risk prostate cancer was defined as Cambridge Prognostic Group (CPG) 4 or 5, or having a Gleason score ≥ 8. Multivariate survival analysis, including age and initial prostate specific antigen levels as covariates, was used to determine the relationship between hypertension status at diagnosis with prostate cancer, prostate cancer risk groups, and metastatic disease. Differential gene expression was performed for hypertension status at diagnosis with prostate cancer and metastatic disease. Immune and stromal cell estimation scores, and Hallmark gene sets, were inferred using patient tumour gene expression profiles. Results and Discussion: Hypertension status at diagnosis with prostate cancer was not associated with metastatic disease. When classifying by Gleason score risk, hypertension had significantly better outcomes for metastatic disease in high-risk patients (HR = 0.43, p-value = 0.009), but not in low- and intermediate-risk patients (HR = 1.86, p-value = 0.18; p-interaction = 0.022). However, when classifying by CPG risk, hypertension was not associated with metastatic disease in high-risk patients or low- and intermediate-risk patients. 142 genes were differentially expressed for hypertension status at diagnosis of prostate cancer (p-value &lt; 0.01), of which 4 were also differentially expressed in relation to metastatic disease (p-value &lt; 0.01). Immune and stromal cell type estimation scores and Hallmark gene sets were not differentially expressed for hypertension status at diagnosis of prostate cancer. Conclusion: Hypertension was protective of metastatic disease in patients diagnosed with high-risk prostate cancer, but not in patients diagnosed with low- and intermediate-risk prostate cancer. Our ongoing analysis will aim to validate these findings in separate independent prostate cancer cohorts and to assess whether the observed associations are influenced by antihypertensive medication use prior to diagnosis. Using hypertension as a surrogate for antihypertensive medication usage, our analysis could potentially suggest antihypertensive medication as repurposed, preventative therapeutics for high-risk prostate cancer. Citation Format: Niamh Murphy, Emma Allott, De","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"213 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006156","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 : 2026-01-20DOI: 10.1158/1538-7445.prostateca26-b082
Fang Xie
Docetaxel is the first-line chemotherapy for metastatic castration-resistant prostate cancer (PC), but clinically meaningful mechanisms of resistance remain to be established. We generated an in vivo model of docetaxel resistance using castration resistant patient-derived xenografts and found increased expression of genes that drive development of multiciliated cells, including FOXJ1 and its effector genes, many of which regulate ciliary microtubules (MTs). Mechanistically, FOXJ1 overexpression conferred docetaxel resistance in vitro and in vivo, which was associated with decreased docetaxel-mediated MT bundling. Overexpression of a MT-associated FOXJ1-regulated gene (TPPP3) had similar effects. Conversely, FOXJ1 knockdown impaired basal MT function, enhanced taxane binding to MTs, and increased docetaxel sensitivity. These results establish mechanistic causality between the FOXJ1 signaling axis, MT biology, and taxane resistance. Clinically, FOXJ1 gene amplification was increased in taxane-treated PC patients. Moreover, in the CHAARTED clinical trial of docetaxel combined with androgen deprivation for metastatic PC, higher baseline FOXJ1 was predictive of decreased survival in PC patients treated with docetaxel, further supporting clinical relevance. Together these findings identify a previously unrecognized clinically impactful mechanism of taxane resistance whose exploitation could stratify patients that will not benefit from taxane treatment. Citation Format: Fang Xie. FOXJ1 mediates taxane resistance through regulation of microtubule dynamics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl): nr B082.
{"title":"Abstract B082: FOXJ1 mediates taxane resistance through regulation of microtubule dynamics","authors":"Fang Xie","doi":"10.1158/1538-7445.prostateca26-b082","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b082","url":null,"abstract":"Docetaxel is the first-line chemotherapy for metastatic castration-resistant prostate cancer (PC), but clinically meaningful mechanisms of resistance remain to be established. We generated an in vivo model of docetaxel resistance using castration resistant patient-derived xenografts and found increased expression of genes that drive development of multiciliated cells, including FOXJ1 and its effector genes, many of which regulate ciliary microtubules (MTs). Mechanistically, FOXJ1 overexpression conferred docetaxel resistance in vitro and in vivo, which was associated with decreased docetaxel-mediated MT bundling. Overexpression of a MT-associated FOXJ1-regulated gene (TPPP3) had similar effects. Conversely, FOXJ1 knockdown impaired basal MT function, enhanced taxane binding to MTs, and increased docetaxel sensitivity. These results establish mechanistic causality between the FOXJ1 signaling axis, MT biology, and taxane resistance. Clinically, FOXJ1 gene amplification was increased in taxane-treated PC patients. Moreover, in the CHAARTED clinical trial of docetaxel combined with androgen deprivation for metastatic PC, higher baseline FOXJ1 was predictive of decreased survival in PC patients treated with docetaxel, further supporting clinical relevance. Together these findings identify a previously unrecognized clinically impactful mechanism of taxane resistance whose exploitation could stratify patients that will not benefit from taxane treatment. Citation Format: Fang Xie. FOXJ1 mediates taxane resistance through regulation of microtubule dynamics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl): nr B082.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"45 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006196","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 : 2026-01-20DOI: 10.1158/1538-7445.prostateca26-b024
Shu Ning, Zachary Schaaf, Masuda Sharifi, Pui-Kai Li, Allen Gao
Background Resistance to current therapies is a significant challenge in advanced prostate cancer. The bromodomain and extra-terminal (BET) subclass of proteins are known to contribute to cancer progression and resistance to standard therapies. To date, intervention strategies for targeting BET proteins on bromodomains using small-molecule inhibitors, specifically acetylated lysine mimics, have been developed to block the binding of BET protein bromodomains to acetylated lysine. Unfortunately, clinical trials have yielded disappointing results characterized by limited efficacy and significant dose-limiting toxicities. Methods: We use docking, surface plasmon resonance (SPR), and affinity precipitation assays to discover the sequence of amino acids for the critical binding moieties on extra-terminal (ET) of BET domain. High-throughput virtual screening is utilized to identify ET-BET binding inhibitors. SPR were used to evaluate the binding affinity and anti-tumor effects in enzalutamide-(MDVR) and darolutamide-resistant (DaroR) cells. Mechanism of action (MOA) of the selected compound BETi-10 was evaluated by transcriptomic sequencing, qRT-PCR, western blotting, and luciferase reporter assay. Alteration of chromatin accessibility by BETi-10 in MDVR cells was determined via ATAC sequencing. Ex vivo and in vivo anti-tumor effects of BETi-10 in LuCaP35CR PDX were evaluated. Results Based on the structure of ET-BET protein interface, ten compounds have been identified through computational screening to effectively inhibit the ET-domain binding. Biological screening on enzalutamide- and darolutamide-resistant cell lines revealed that BETi-10 as the most potent inhibitory compound. RNAseq analysis showed that the top downregulated pathways by BETi-10 include Myc and E2F pathways. ATAC-seq and ChIP-seq analysis has shown that BETi-10 decreases the genome-wide chromatin accessibility in MDVR cells. Ex vivo and in vivo study in LuCaP35CR PDX model demonstrated that BETi-10 effectively inhibits the growth of organoids and tumor, synergizes with enzalutamide and has better safety profile than current BET inhibitor. Conclusions In this study, we have developed BETi-10, a first-in-class small-molecule inhibitor targeting the ET domain of BET proteins. Our findings show that targeting BET/BRD4 by BETi-10 suppresses resistant tumor viability in vitro and in vivo, providing a novel therapeutic strategy for advanced prostate cancer patients. Citation Format: Shu Ning, Zachary Schaaf, Masuda Sharifi, Pui-Kai Li, Allen Gao. Novel therapeutics targeting BET-mediated oncogenesis in lethal prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl): nr B024.
{"title":"Abstract B024: Novel therapeutics targeting BET-mediated oncogenesis in lethal prostate cancer","authors":"Shu Ning, Zachary Schaaf, Masuda Sharifi, Pui-Kai Li, Allen Gao","doi":"10.1158/1538-7445.prostateca26-b024","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b024","url":null,"abstract":"Background Resistance to current therapies is a significant challenge in advanced prostate cancer. The bromodomain and extra-terminal (BET) subclass of proteins are known to contribute to cancer progression and resistance to standard therapies. To date, intervention strategies for targeting BET proteins on bromodomains using small-molecule inhibitors, specifically acetylated lysine mimics, have been developed to block the binding of BET protein bromodomains to acetylated lysine. Unfortunately, clinical trials have yielded disappointing results characterized by limited efficacy and significant dose-limiting toxicities. Methods: We use docking, surface plasmon resonance (SPR), and affinity precipitation assays to discover the sequence of amino acids for the critical binding moieties on extra-terminal (ET) of BET domain. High-throughput virtual screening is utilized to identify ET-BET binding inhibitors. SPR were used to evaluate the binding affinity and anti-tumor effects in enzalutamide-(MDVR) and darolutamide-resistant (DaroR) cells. Mechanism of action (MOA) of the selected compound BETi-10 was evaluated by transcriptomic sequencing, qRT-PCR, western blotting, and luciferase reporter assay. Alteration of chromatin accessibility by BETi-10 in MDVR cells was determined via ATAC sequencing. Ex vivo and in vivo anti-tumor effects of BETi-10 in LuCaP35CR PDX were evaluated. Results Based on the structure of ET-BET protein interface, ten compounds have been identified through computational screening to effectively inhibit the ET-domain binding. Biological screening on enzalutamide- and darolutamide-resistant cell lines revealed that BETi-10 as the most potent inhibitory compound. RNAseq analysis showed that the top downregulated pathways by BETi-10 include Myc and E2F pathways. ATAC-seq and ChIP-seq analysis has shown that BETi-10 decreases the genome-wide chromatin accessibility in MDVR cells. Ex vivo and in vivo study in LuCaP35CR PDX model demonstrated that BETi-10 effectively inhibits the growth of organoids and tumor, synergizes with enzalutamide and has better safety profile than current BET inhibitor. Conclusions In this study, we have developed BETi-10, a first-in-class small-molecule inhibitor targeting the ET domain of BET proteins. Our findings show that targeting BET/BRD4 by BETi-10 suppresses resistant tumor viability in vitro and in vivo, providing a novel therapeutic strategy for advanced prostate cancer patients. Citation Format: Shu Ning, Zachary Schaaf, Masuda Sharifi, Pui-Kai Li, Allen Gao. Novel therapeutics targeting BET-mediated oncogenesis in lethal prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl): nr B024.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"31 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006249","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 : 2026-01-16DOI: 10.1158/0008-5472.can-25-4381
Pan-Yu Chen, Gideon Bollag
Targeted inhibition of mutant BRAF has transformed the management of BRAF-V600–mutant melanoma and other malignancies, with multiple ATP-competitive kinase inhibitors now approved for clinical use. Despite their clinical success, these agents are limited by intrinsic and acquired resistance, paradoxical activation of the MAPK pathway, and dose-limiting toxicities. The development of BRAF-V600X oncoprotein–selective degraders offers a mechanistically distinct therapeutic approach that may bypass several of these liabilities. Thus, the discovery of an orally bioavailable mutant BRAF-selective degrader is highly sought after. In this issue of Cancer Research, Kreger and colleagues developed CFT1946, a clinical-stage, highly potent, RAF family–selective degrader that is effective in various cellular and xenograft models. Importantly, CFT1946 is active in the privileged central nervous system environment, accessing a common site of metastasis for BRAF-mutant melanomas. By eliminating the BRAF-V600X oncoprotein, CFT1946 can overcome RAF dimer– and EGFR-driven resistance to standard inhibitors. Although the mechanism of mutant selectivity is unclear, this compound exhibits a promising therapeutic index by sparing wild-type RAF proteins in cells. As CFT1946 progresses through clinical development, the field of oncoprotein-specific degradation will mature. See related article by Kreger et al., p. 438
{"title":"Overcoming the Limits of Inhibition: Mutant-Selective BRAF Degraders","authors":"Pan-Yu Chen, Gideon Bollag","doi":"10.1158/0008-5472.can-25-4381","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-4381","url":null,"abstract":"Targeted inhibition of mutant BRAF has transformed the management of BRAF-V600–mutant melanoma and other malignancies, with multiple ATP-competitive kinase inhibitors now approved for clinical use. Despite their clinical success, these agents are limited by intrinsic and acquired resistance, paradoxical activation of the MAPK pathway, and dose-limiting toxicities. The development of BRAF-V600X oncoprotein–selective degraders offers a mechanistically distinct therapeutic approach that may bypass several of these liabilities. Thus, the discovery of an orally bioavailable mutant BRAF-selective degrader is highly sought after. In this issue of Cancer Research, Kreger and colleagues developed CFT1946, a clinical-stage, highly potent, RAF family–selective degrader that is effective in various cellular and xenograft models. Importantly, CFT1946 is active in the privileged central nervous system environment, accessing a common site of metastasis for BRAF-mutant melanomas. By eliminating the BRAF-V600X oncoprotein, CFT1946 can overcome RAF dimer– and EGFR-driven resistance to standard inhibitors. Although the mechanism of mutant selectivity is unclear, this compound exhibits a promising therapeutic index by sparing wild-type RAF proteins in cells. As CFT1946 progresses through clinical development, the field of oncoprotein-specific degradation will mature. See related article by Kreger et al., p. 438","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"20 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986255","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 : 2026-01-16DOI: 10.1158/0008-5472.CAN-25-5025
Xiaoli Liu, Bonan Chen, Fuda Xie, Kit Yee Wong, Alvin H K Cheung, Jinglin Zhang, Qian Wu, Canbin Fang, Jintao Hu, Shouyu Wang, Dazhi Xu, Jianwu Chen, Yuzhi Wang, Chi Chun Wong, Huarong Chen, William K K Wu, Jun Yu, Michael W Y Chan, Chi Man Tsang, Kwok Wai Lo, Gary M K Tse, Ka-Fai To, Wei Kang
{"title":"Correction: FOXP4 Is a Direct YAP1 Target That Promotes Gastric Cancer Stemness and Drives Metastasis.","authors":"Xiaoli Liu, Bonan Chen, Fuda Xie, Kit Yee Wong, Alvin H K Cheung, Jinglin Zhang, Qian Wu, Canbin Fang, Jintao Hu, Shouyu Wang, Dazhi Xu, Jianwu Chen, Yuzhi Wang, Chi Chun Wong, Huarong Chen, William K K Wu, Jun Yu, Michael W Y Chan, Chi Man Tsang, Kwok Wai Lo, Gary M K Tse, Ka-Fai To, Wei Kang","doi":"10.1158/0008-5472.CAN-25-5025","DOIUrl":"10.1158/0008-5472.CAN-25-5025","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"86 2","pages":"556"},"PeriodicalIF":16.6,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12809110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988087","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 : 2026-01-14DOI: 10.1158/0008-5472.can-25-3092
Fangli Liao, Yanran Tong, Hua Sun, Sen Chen, Siyang Wen, Yan-e Du, Linshan Jiang, Tong Huang, Manran Liu, Weixian Chen, Liping Yang
The immunosuppressive tumor microenvironment (TME) enables cancer cells to evade clinical immunotherapies. Neural networks are vital components of the TME, and interactions between cancer cells, neuronal cells, and immune cells mediate immunosuppression. Hence, understanding the mechanisms of intercellular crosstalk could inform immunomodulatory approaches to enhance immunotherapy efficacy. Here, we found that the vagus nerve regulated the crosstalk between gastric cancer (GC) cells and group 3 innate lymphoid cells (ILC3s), boosting immune resistance in GC by enhancing programmed death ligand 1 (PD-L1) expression. Specifically, the infiltrated vagus nerve released acetylcholine (ACh) that elevated the expression of lipase ABHD16A in GC cells, facilitating the production and secretion of the metabolite lysophosphatidylserine (LysoPS) into the TME. LysoPS facilitated the proliferation and activation of ILC3s in TME, resulting in production of the cytokine interleukin (IL)-22 via the GPR34/AKT/STAT3 axis. In turn, IL-22 triggered the unfolded protein response (UPR) in GC cells, which led to an increase in PD-L1 expression that enhanced immune resistance. Importantly, targeting ACh or the crosstalk between GC cells and ILC3s significantly enhanced the efficacy of anti-PD-L1 immunotherapy. Serum levels of LysoPS and IL-22 were elevated in GC patients, particularly those with perineural invasion. Collectively, these findings provide valuable insights into the crosstalk between GC cells, nerve cells, and ILC3s that regulates immunosuppression and response to ant-PD-L1 immunotherapy, emphasizing the potential clinical significance of this axis for detecting and treating GC.
{"title":"Nerves Stimulates Crosstalk between Gastric Cancer and Group 3 Innate Lymphoid Cells to Enhance Immunosuppression","authors":"Fangli Liao, Yanran Tong, Hua Sun, Sen Chen, Siyang Wen, Yan-e Du, Linshan Jiang, Tong Huang, Manran Liu, Weixian Chen, Liping Yang","doi":"10.1158/0008-5472.can-25-3092","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-3092","url":null,"abstract":"The immunosuppressive tumor microenvironment (TME) enables cancer cells to evade clinical immunotherapies. Neural networks are vital components of the TME, and interactions between cancer cells, neuronal cells, and immune cells mediate immunosuppression. Hence, understanding the mechanisms of intercellular crosstalk could inform immunomodulatory approaches to enhance immunotherapy efficacy. Here, we found that the vagus nerve regulated the crosstalk between gastric cancer (GC) cells and group 3 innate lymphoid cells (ILC3s), boosting immune resistance in GC by enhancing programmed death ligand 1 (PD-L1) expression. Specifically, the infiltrated vagus nerve released acetylcholine (ACh) that elevated the expression of lipase ABHD16A in GC cells, facilitating the production and secretion of the metabolite lysophosphatidylserine (LysoPS) into the TME. LysoPS facilitated the proliferation and activation of ILC3s in TME, resulting in production of the cytokine interleukin (IL)-22 via the GPR34/AKT/STAT3 axis. In turn, IL-22 triggered the unfolded protein response (UPR) in GC cells, which led to an increase in PD-L1 expression that enhanced immune resistance. Importantly, targeting ACh or the crosstalk between GC cells and ILC3s significantly enhanced the efficacy of anti-PD-L1 immunotherapy. Serum levels of LysoPS and IL-22 were elevated in GC patients, particularly those with perineural invasion. Collectively, these findings provide valuable insights into the crosstalk between GC cells, nerve cells, and ILC3s that regulates immunosuppression and response to ant-PD-L1 immunotherapy, emphasizing the potential clinical significance of this axis for detecting and treating GC.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"41 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968591","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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