Neoplasia最新文献_第3页

Dynasore as a dual modulator of lipid rafts and cell death in pancreatic cancer Dynasore作为胰腺癌脂筏和细胞死亡的双重调节剂。

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-11-15 DOI: 10.1016/j.neo.2025.101254

Jakob S. Hamilton , Rekha R. Garg , Ryan M. Thomas

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States and predicted to soon surpass colorectal cancer as the second. The lack of screening tests, advanced stage at diagnosis, and resistance to current treatment regimens underscore the urgent need for novel therapeutic strategies. Targeting lipid rafts, which are specialized membrane microdomains integral to cancer-related processes such as the epithelial-mesenchymal transition, angiogenesis, and metastatic dissemination, offers a promising strategy to combat this deadly disease. As these catalytic platforms regulate signal transduction pathways key to both cell survival and chemoresistance, we investigated the effects of their disruption on PDAC programmed cell death and proliferation using the dynamin inhibitor, Dynasore. In a panel of human PDAC cell lines, Dynasore reduced lipid rafts in the plasma membrane, resulting in increased oxidative and proteotoxic stress which activated the ATR-Chk1 DNA damage response and initiated programmed cell death. Caspase-1 activation led to pyroptosis in the human PDAC cell lines, BxPC-3 and MIA PaCa-2, while Caspase-3 activation induced apoptosis in MIA PaCa-2 and L3.6pl. These cell-specific cell death responses resulted in dose- and time-dependent antiproliferative effects that enhanced gemcitabine cytotoxicity. Our findings suggest that lipid raft inhibition can modulate proliferation, distinct cell death pathways, and treatment response in PDAC. Given the limitations of current therapies, these results emphasize the need for further investigation into lipid raft-targeting agents in combination with chemotherapy to overcome chemoresistance in pancreatic cancer.

Significance

Dynasore exerts potent anti-proliferative and synergistic effects with gemcitabine in vitro by disrupting lipid rafts and differentially inducing programmed cell death, highlighting its potential as a novel therapy in PDAC.

胰腺导管腺癌（PDAC）是美国癌症相关死亡的第三大原因，预计很快将超过结肠直肠癌成为第二大原因。筛查试验的缺乏、诊断阶段较晚以及对当前治疗方案的耐药性强调了迫切需要新的治疗策略。脂筏是肿瘤相关过程（如上皮-间质转化、血管生成和转移性传播）中不可或缺的特殊膜微结构域，靶向脂筏为对抗这种致命疾病提供了一种有希望的策略。由于这些催化平台调节细胞存活和化疗耐药的关键信号转导通路，我们使用动力蛋白抑制剂Dynasore研究了它们的破坏对PDAC程序性细胞死亡和增殖的影响。在一组人类PDAC细胞系中，Dynasore减少了质膜中的脂筏，导致氧化和蛋白毒性应激增加，从而激活ATR-Chk1 DNA损伤反应并启动程序性细胞死亡。Caspase-1激活导致人PDAC细胞系、BxPC-3和MIA PaCa-2细胞凋亡，Caspase-3激活导致MIA PaCa-2和L3.6pl细胞凋亡。这些细胞特异性的细胞死亡反应导致剂量和时间依赖性的抗增殖作用，增强了吉西他滨的细胞毒性。我们的研究结果表明，脂质筏抑制可以调节PDAC的增殖、不同的细胞死亡途径和治疗反应。鉴于目前治疗方法的局限性，这些结果强调需要进一步研究脂质筏靶向药物联合化疗以克服胰腺癌的化疗耐药。意义：Dynasore通过破坏脂筏和差异诱导程序性细胞死亡，在体外与吉西他滨发挥强大的抗增殖和协同作用，突出了其作为PDAC新疗法的潜力。

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引用次数: 0

Corrigendum to “P53-independent partial restoration of the p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation by ERK1/2 and CDK9” [Neoplasia, volume 23 (2021) 304325] “通过ERK1/2和CDK9的ATF4转录调节，p53突变肿瘤中p53通路的p53独立部分恢复”的勘误表[Neoplasia， vol . 23 (2021) 304325]

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-11-14 DOI: 10.1016/j.neo.2025.101249

Xiaobing Tian , Nagib Ahsan , Amriti Lulla , Avital Lev , Philip Abbosh , David T. Dicker , Shengliang Zhang , Wafik S. El-Deiry

引用次数: 0

Oral bioavailable ITRI-148 degrades androgen receptor variants and overcomes antiandrogen resistance in advanced prostate cancer 口服生物可利用ITRI-148降解雄激素受体变异并克服晚期前列腺癌的抗雄激素耐药

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-11-13 DOI: 10.1016/j.neo.2025.101253

Chiu-Lien Hung , Wen-Ning Hsu , Tsan-Chun Wang , Wan-Ru Chen , Yu-Ting Chen , Zong-Keng Kuo , Tsan-Lin Hu , Yu-Chin Lin , Hsun-Hao Yeh , Han-Chen Lin , Chia-Jung Yu , Chih-Wei Fu , Hao-Hsuan Liu , Hung-Chih Hsu , Po-Hung Lin , See-Tong Pang , Chih-Ho Lai , Ling-Yu Wang

Androgen receptor (AR) signaling remains a key driver of castration-resistant prostate cancer (CRPC), with AR splice variants like AR-V7 contributing to resistance against second-generation antiandrogens. Targeting the AR N-terminal domain (NTD) provides a strategy to bypass ligand-binding domain (LBD)-mediated resistance. We developed ITRI-148, a CRBN-based AR-NTD degrader incorporating a rigid piperidine-alkyne linker optimized for oral pharmacokinetics. ITRI-148 efficiently degrades full-length AR, AR-V7, and clinically relevant mutants (L702H, H875Y). It facilitates the recruitment of active AR species to CRBN in the nucleus, promoting their polyubiquitination and proteasomal degradation. In CRPC and enzalutamide-resistant models, ITRI-148 robustly suppresses AR signaling and inhibits cell viability, outperforming enzalutamide. With long-term treatment, it achieves sustained AR suppression without inducing compensatory AR-V7 upregulation or PSA re-expression. In vivo, ITRI-148 demonstrates potent antitumor efficacy in both castrated and hormone-intact CRPC models, supported by favorable pharmacokinetic properties, stability and safety profiles. These findings position ITRI-148 as a promising next-generation AR-targeting agent capable of degrading resistant AR variants and providing durable inhibition of AR signaling in advanced prostate cancer.

雄激素受体（AR）信号仍然是去势抵抗性前列腺癌（CRPC）的关键驱动因素，AR- v7等AR剪接变异体有助于抵抗第二代抗雄激素。靶向AR n端结构域（NTD）提供了一种绕过配体结合结构域（LBD）介导的抗性的策略。我们开发了ITRI-148，一种基于crbn的AR-NTD降解剂，结合了一种针对口服药代动力学优化的刚性哌啶-炔连接剂。ITRI-148能有效降解全长AR、AR- v7和临床相关突变（L702H、H875Y）。它促进了活性AR物种在细胞核中向CRBN募集，促进它们的多泛素化和蛋白酶体降解。在CRPC和enzalutamide耐药模型中，ITRI-148强有力地抑制AR信号和抑制细胞活力，优于enzalutamide。通过长期治疗，它可以实现持续的AR抑制，而不会诱导代偿性AR- v7上调或PSA重新表达。在体内，ITRI-148在阉割和激素完整的CRPC模型中都显示出强大的抗肿瘤功效，具有良好的药代动力学特性、稳定性和安全性。这些发现将ITRI-148定位为有前景的下一代AR靶向药物，能够降解耐药AR变体，并在晚期前列腺癌中提供持久的AR信号抑制。

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引用次数: 0

Corrigendum to “6-Aminonicotinamide, a G6PD inhibitor, mitigates CAPS1 reduction mediated HCC metastasis via ERK and GSK3β signals” [Neoplasia volume 70 (2025) 101239] “6-氨基烟酰胺，一种G6PD抑制剂，通过ERK和GSK3β信号减轻CAPS1减少介导的HCC转移”[Neoplasia vol 70(2025) 101239]的更正。

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-11-06 DOI: 10.1016/j.neo.2025.101247

Xiahui Lin , Yingying Xu , Encheng Bai , Yiran Deng , Wei Zhang , Ruyi Xue , Si Zhang , Li Zhang , Wenqing Tang , Ling Dong , She Chen

引用次数: 0

Oral AZD5438 is a clinically translatable otoprotectant against cisplatin-induced hearing loss 口服AZD5438是一种临床可翻译的抗顺铂性听力损失的耳保护剂。

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-11-03 DOI: 10.1016/j.neo.2025.101250

Yunlong Huang , Xintian Zhang , Enrick Vesanes , Tal Teitz , Jian Zuo

Cisplatin-based chemotherapy causes hearing loss in 40–60 % of all patients, yet effective preventative options remain limited. Building on prior animal studies, we demonstrate that oral administration of AZD5438, a potent and selective CDK2 inhibitor, provides dose-dependent protection against hearing loss in a clinically relevant multi-dose cisplatin mouse model. Protective doses (4.7 and 9.4 mg/kg b.i.d.) fall within the human-equivalent maximum tolerated dose range established in AstraZeneca trials, and exhibit plasma pharmacokinetics comparable to those in humans. Importantly, AZD5438 at 9.4 mg/kg b.i.d. does not reduce cisplatin’s anti-tumor efficacy in a testicular cancer xenograft model, consistent with in vitro findings. These results support AZD5438 as a promising candidate for clinical trials to prevent cisplatin-induced hearing loss while preserving cancer treatment efficacy.

以顺铂为基础的化疗导致40- 60%的患者听力损失，但有效的预防选择仍然有限。基于先前的动物研究，我们证明口服AZD5438（一种强效和选择性CDK2抑制剂）在临床相关的多剂量顺铂小鼠模型中提供剂量依赖性听力损失保护。保护剂量（每天4.7和9.4 mg/kg b.i.d）在阿斯利康试验中确定的人体等效最大耐受剂量范围内，并显示出与人体相当的血浆药代动力学。重要的是，在睾丸癌异种移植模型中，9.4 mg/kg剂量的AZD5438不会降低顺铂的抗肿瘤疗效，这与体外研究结果一致。这些结果支持AZD5438作为一种有希望的临床试验候选者，在保持癌症治疗效果的同时预防顺铂性听力损失。

引用次数: 0

PDGFRα governs multiple cellular signals and plays a protective role in tumor progression PDGFRα调控多种细胞信号并在肿瘤进展中发挥保护作用。

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-11-03 DOI: 10.1016/j.neo.2025.101248

Masao Hayashi , Noriko Okuno , Le Thi Thu Trang , Ayaka Inami , Yosei Kato , Takeru Hamashima , Dang Son Tung , Yasuharu Watanabe , Rieko Kojima , Miwa Fujikawa , Akari Ejiri , Tomomi Kunisawa , Fumiko Itoh , Masashi Muramatsu , Tran Ngoc Dung , Dang Thanh Chung , Pham Van Thinh , Takeharu Minamitani , Tsutomu Yanagibashi , Toshihiko Fujimori , Seiji Yamamoto

Extensive research has been done on the molecular mechanisms of tumor development and growth. However, multiple aspects remain elusive. We examined cellular signaling mechanisms involving platelet-derived growth factor (PDGF) and its receptor (PDGFR), using adult PDGFRα conditional knockout (α-KO) mice implanted with Lewis lung carcinoma (LLC) cells, which express PDGFRα. Unexpectedly, α-KO mice exhibited larger tumors and extensive lung metastasis compared to control mice. Mechanistically, under the activation of PDGF-BB-PDGFRα signal axis in LLC cells, transforming growth factor-α (TGF-α) induced accelerated tumor growth via epidermal growth factor receptor (EGFR) signal. Insufficient vascular development with lower pericyte coverage was also noted, leading to hypoxia and increased expression of transforming growth factor-β (TGF-β), which induced as a critical signaling molecule determining lung metastatic changes with the AKT1 activity. Our findings suggested that PDGFRα in interstitial cells may serve a protective role against tumor progression and selective inhibition of PDGFRα in tumor cells could offer a more targeted therapeutic approach for cancer patients. Statement of significance: PDGFRα in interstitial cells in tumors governs multiple cellular signals such as PDGF-BB, TGF-α, and TGF-β and plays a protective role in tumor progression.

人们对肿瘤发生和生长的分子机制进行了广泛的研究。然而，许多方面仍然难以捉摸。我们研究了涉及血小板衍生生长因子（PDGF）及其受体（PDGFR）的细胞信号传导机制，使用成年PDGFRα条件敲除（α-KO）小鼠植入表达PDGFRα的Lewis肺癌（LLC）细胞。出乎意料的是，α-KO小鼠比对照组小鼠表现出更大的肿瘤和广泛的肺转移。机制上，在LLC细胞PDGF-BB-PDGFRα信号轴激活下，转化生长因子-α (TGF-α)通过表皮生长因子受体（EGFR）信号诱导肿瘤加速生长。血管发育不足，周细胞覆盖率低，导致缺氧和转化生长因子-β (TGF-β)的表达增加，TGF-β是决定肺转移变化的关键信号分子，与AKT1活性有关。我们的研究结果表明，间质细胞中的PDGFRα可能对肿瘤进展具有保护作用，选择性抑制肿瘤细胞中的PDGFRα可能为癌症患者提供更有针对性的治疗方法。意义说明：肿瘤间质细胞PDGFRα调控PDGF-BB、TGF-α、TGF-β等多种细胞信号，在肿瘤进展中起保护作用。

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引用次数: 0

A calcium-sensing MCTP1/FYN/MEF2C circuit drives therapy-induced neuroendocrine prostate cancer 钙敏感MCTP1/FYN/MEF2C电路驱动治疗诱导的神经内分泌前列腺癌

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-11-01 DOI: 10.1016/j.neo.2025.101251

Phan Vu Thuy Dung , Wei-Yu Chen , Ming-Kun Liu , Shauh-Der Yeh , Gagan Kajla , Hsiu-Lien Yeh , Wei-Hao Chen , Kuo-Ching Jiang , Han-Ru Li , Cheng-Sheng Chen , Himisha Beltran , Yu-Ching Wen , Yen-Nien Liu

Neuroendocrine prostate cancer (NEPC) represents a highly aggressive, treatment‑refractory phenotype that frequently emerges after androgen‑deprivation therapy (ADT). Although perturbed calcium signaling has been implicated in prostate cancer bone metastasis, the specific molecular mechanisms governing NEPC progression remain incompletely characterized. Here, we delineate the MCTP1/FYN/MEF2C signaling axis as a pivotal modulator of intracellular calcium homeostasis that drives neuroendocrine differentiation (NED) and enhances tumor aggressiveness. We demonstrate that ADT upregulates MCTP1, a transmembrane protein with calcium-sensing capabilities, which subsequently activates the Src-family kinase FYN to initiate oncogenic signaling cascades. This activation induces transcriptional upregulation of bone morphogenesis-related genes, including MEF2C and ALPL. Mechanistically, calcium-responsive transcription factors ZEB1 and ZEB2 directly transactivate MEF2C, thereby integrating calcium flux with epithelial-to-mesenchymal transition (EMT) programs in prostate cancer. Elevated ZEB1/ZEB2-dependent MEF2C expression reinforces the MCTP1/FYN kinase pathway, potentiating neuroendocrine lineage commitment and ALPL enzymatic activity. Chromatin immunoprecipitation coupled with transcriptomic analyses reveals that MEF2C directly occupies regulatory elements of MCTP1, FYN, and ALPL, enabling their calcium-dependent transcriptional activation. Structure-based virtual screening identified a potent small-molecule antagonist targeting MCTP1, which markedly attenuates tumor burden, ALPL activity, and neuroendocrine marker expression in prostate cancer in vitro and in vivo models. Collectively, these findings establish MCTP1 as a novel therapeutically exploitable vulnerability in therapy-induced NEPC, providing critical insights into the calcium-dependent oncogenic signaling networks mediated by the MCTP1/FYN/MEF2C axis in advanced prostate cancer.

神经内分泌前列腺癌（NEPC）是一种高度侵袭性、治疗难治性的表型，经常在雄激素剥夺治疗（ADT）后出现。尽管受干扰的钙信号与前列腺癌骨转移有关，但控制NEPC进展的特定分子机制仍未完全确定。在这里，我们描述了MCTP1/FYN/MEF2C信号轴作为驱动神经内分泌分化（NED）和增强肿瘤侵袭性的细胞内钙稳态的关键调节剂。我们证明ADT上调MCTP1，一种具有钙感知能力的跨膜蛋白，随后激活src家族激酶FYN启动致癌信号级联反应。这种激活诱导骨形态发生相关基因的转录上调，包括MEF2C和ALPL。在机制上，钙响应转录因子ZEB1和ZEB2直接反激活MEF2C，从而将钙通量与前列腺癌上皮-间质转化（EMT）程序结合起来。升高的ZEB1/ zeb2依赖性MEF2C表达增强了MCTP1/FYN激酶途径，增强了神经内分泌谱系的承诺和ALPL酶活性。染色质免疫沉淀结合转录组学分析显示，MEF2C直接占据MCTP1、FYN和ALPL的调控元件，使其钙依赖性转录激活。基于结构的虚拟筛选发现了一种有效的靶向MCTP1的小分子拮抗剂，该拮抗剂在体外和体内前列腺癌模型中显著降低肿瘤负荷、ALPL活性和神经内分泌标志物的表达。总之，这些发现确立了MCTP1在治疗诱导的NEPC中是一种新的治疗可利用的易感性，为晚期前列腺癌中由MCTP1/FYN/MEF2C轴介导的钙依赖性致癌信号网络提供了重要的见解。

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引用次数: 0

Identification of BET inhibitors (BETi) against solitary fibrous tumor (SFT) through high-throughput screening (HTS) 通过高通量筛选（HTS）鉴定抗孤立性纤维肿瘤（SFT）的BET抑制剂（BETi）。

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-10-29 DOI: 10.1016/j.neo.2025.101244

Jose L. Mondaza-Hernandez , David S. Moura , Yi Li , Jesus L. Marti , Paulino Gomez-Puertas , John T. Nguyen , Shuguang Wei , Bruce A. Posner , Clark A. Meyer , Leonidas Bleris , Javier Martin-Broto , Heather N. Hayenga

Cancers, especially fusion oncoprotein (FO)-driven hematological cancers and sarcomas, often develop from a low number of key mutations. Solitary Fibrous Tumor (SFT) is a rare mesenchymal tumor driven by the NAB2-STAT6 oncofusion gene. Currently, the treatment options for SFT remain limited, with anti-angiogenic drugs providing only partial responses with an average survival of two years. We constructed SFT cell models harboring specific NAB2-STAT6 fusion transcripts using the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology, and we used these cells as models of SFT. High-throughput drug screens demonstrated that the BET inhibitor Mivebresib can differentially reduce proliferation in SFT cell models. Subsequently, BET inhibitors Mivebresib and BMS-986158 efficiently reduced tumor growth in an SFT patient-derived xenograft (PDX) animal model. Furthermore, our data showed that NAB2-STAT6 fusions may lead to high levels of DNA damage in SFTs. Consequently, combining BET inhibitors with PARP (Poly (ADP-ribose) polymerase) inhibitors or with ATR inhibitors significantly enhanced anti-proliferative effects in SFT cells. Taken together, this study establishes BET inhibitors Mivebresib and BMS-986158 as promising anti-SFT agents.

癌症，特别是融合癌蛋白（FO）驱动的血液学癌症和肉瘤，通常由少量关键突变发展而来。孤立性纤维瘤（SFT）是一种罕见的由NAB2-STAT6混淆基因驱动的间质肿瘤。目前，SFT的治疗选择仍然有限，抗血管生成药物只能提供部分反应，平均生存期为两年。我们使用CRISPR （Clustered Regularly Interspaced Short Palindromic Repeats）技术构建了含有特定NAB2-STAT6融合转录本的SFT细胞模型，并将这些细胞用作SFT模型。高通量药物筛选表明，BET抑制剂Mivebresib可以不同程度地减少SFT细胞模型的增殖。随后，BET抑制剂Mivebresib和BMS-986158在SFT患者来源的异种移植（PDX）动物模型中有效地降低了肿瘤生长。此外，我们的数据显示，NAB2-STAT6融合可能导致SFTs中高水平的DNA损伤。因此，将BET抑制剂与PARP（聚（adp -核糖）聚合酶）抑制剂或ATR抑制剂联合使用可显著增强SFT细胞的抗增殖作用。综上所述，本研究确定BET抑制剂Mivebresib和BMS-986158是有前景的抗sft药物。

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引用次数: 0

Cholesterol biosynthesis as a drug-induced vulnerability in diffuse large B cell lymphoma insensitive to EZH2 inhibition 胆固醇生物合成在对EZH2抑制不敏感的弥漫性大B细胞淋巴瘤中作为药物诱导的易感性。

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-10-27 DOI: 10.1016/j.neo.2025.101243

Rachele Niccolai , Camiel Göbel , Klevis Ndoj , Maaike Kreft , Hendrik J. Kuiken , Cor Lieftink , Ben Morris , Sietse D. Yska , Sebastian Hendrix , Bram van den Broek , Vincent Pappalardo , Marie José Kersten , Roderick L. Beijersbergen , Noam Zelcer , Fred van Leeuwen , Heinz Jacobs

The methyltransferase EZH2 is a critical epigenetic writer in Germinal Center B cell-like Diffuse Large B Cell Lymphoma (GCB-DLBCL). Clinically and experimentally, GCB-DLBCLs are either sensitive or insensitive to EZH2 inhibition. We hypothesized that EZH2 inhibitor (EZH2i) exposure of the insensitive subset may unfold epi‑drug induced, therapeutically exploitable dependencies. An EZH2i-anchored CRISPR-Cas9 drop-out screen identified the cholesterol biosynthesis pathway as an essential co-target in sensitizing EZH2i-insensitive GCB-DLBCLs. Mechanistic investigations into this metabolic dependency revealed that the loss of EZH2 activity impairs the exogenous cholesterol uptake due to reduced surface expression of the low-density lipoprotein (LDL) receptor, which accumulated in the lysosomal compartment. The reduced LDL uptake failed to upregulate SREBP2-mediated cholesterol biosynthesis as a compensatory response, rendering cells sensitive to cholesterol biosynthesis inhibition. In support of this, inhibition of EZH2 of cholesterol biosynthesis-deficient GCB-DLBCL xenograft increased tumor survival. Together, our findings identified the cholesterol biosynthesis pathway as a targetable vulnerability specific to EZH2i-insensitive GCB-DLBCL. These data support future translational studies to determine how clinically approved cholesterol inhibitors can be used to improve treatment outcomes for DLBCL patients non-responsive to EZH2 inhibition.

甲基转移酶EZH2在生发中心B细胞样弥漫性大B细胞淋巴瘤（GCB-DLBCL）中是一个重要的表观遗传书写者。临床和实验表明，gcb - dlbcl对EZH2抑制敏感或不敏感。我们假设EZH2抑制剂（EZH2i）暴露于不敏感亚群可能会揭示外源性药物诱导的、治疗上可利用的依赖性。一项ezh2i锚定的CRISPR-Cas9退出筛选发现，胆固醇生物合成途径是致敏ezh2i不敏感的gcb - dlbcl的重要共同靶点。对这种代谢依赖性的机制研究表明，由于低密度脂蛋白（LDL）受体的表面表达减少，EZH2活性的丧失损害了外源性胆固醇的摄取，这种低密度脂蛋白（LDL）受体积聚在溶酶体腔室中。低密度脂蛋白摄取的减少未能上调srebp2介导的胆固醇生物合成作为代偿反应，使细胞对胆固醇生物合成抑制敏感。为了支持这一点，抑制胆固醇生物合成缺陷的GCB-DLBCL异种移植物的EZH2增加了肿瘤存活率。总之，我们的研究结果确定了胆固醇生物合成途径是ezh2i不敏感的GCB-DLBCL特异性的可靶向脆弱性。这些数据支持未来的转化研究，以确定临床批准的胆固醇抑制剂如何用于改善对EZH2抑制无反应的DLBCL患者的治疗结果。

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引用次数: 0

EGFL6 is a novel HER3 ligand, inducing HER3/integrin heterodimers to induce pERK centrosomal deposition and therapeutic resistance EGFL6是一种新的HER3配体，可诱导HER3/整合素异源二聚体诱导pERK中心体沉积和治疗耐药性。

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-10-27 DOI: 10.1016/j.neo.2025.101246

Shoumei Bai , Navneet Gupta , Victoria Liu , Adetunji Fayomi , Stacy McGonigal , Ronald J. Buckanovich

EGF-like domain multiple-6 (EGFL6) is a secreted tumor growth/migration factor linked with poor outcomes in many tumor types. While EGFL6 is known to signal, in part, via its integrin-binding RGD domain, little else is known about EGFL6 receptors. We evaluated putative EGFL6 receptors and found that EGFL6 treatment of ovarian cancer cells leads to both transient phosphorylation of EGFR and prolonged phosphorylation of HER2 and HER3 and subsequent phosphorylation of ERK (pERK). We found that EGFL6 directly binds HER3. However, EGFL6-driven prolonged activation of HER3 is dependent on an intact EGFL6 integrin-binding RGD domain. Immunoprecipitation and proximity ligation assays confirmed that EGFL6 treatment of cancer cells induces HER2/3-integrin-β3 heterocomplexes. Suggesting EGFL6 could play a role in resistance to HER targeting therapies, EGFL6 is upregulated in EGFR/HER receptor inhibitor-resistant cells, and EGFL6 treatment increases resistance to EGFR/HER inhibitors in vitro. Interestingly, we found that, in EGFL6-treated ovarian cancer cells undergoing mitosis, pERK localizes to the centrosome. Both EGFL6-neutralizing antibodies and HER protein-targeted inhibitors resulted in aberrant pERK centrosomal localization with associated altered mitotic spindle alignment and mitotic catastrophe. Furthermore, combination anti-EGFL6 therapy with the pan-EGFR receptor inhibitor neratinib, compared to either therapy alone, led to an increase in aberrant pERK localization and cancer cell death in vitro and significant restricted tumor growth in vivo. Combined, our data suggests that EGFL6 is a new ligand for HER3 and that dual targeting of the EGFL6/HER signaling axis, via altered pERK localization, may be an effective therapeutic strategy in ovarian cancer.

Significance

This work reveals that EGFL6 is a previously unrecognized ligand for HER3 which can increase resistance to HER family-targeted therapy. We also reveal a novel function of pERK downstream of pHER3 at the centrosome in mitosis. Importantly, we show that EGFL6 is an important therapeutic target to enhance the efficacy of EGFR/HER-targeted therapy.

egf样结构域多重6 （EGFL6）是一种分泌性肿瘤生长/迁移因子，与许多肿瘤类型的不良预后相关。虽然已知EGFL6部分通过其整合素结合RGD结构域发出信号，但对EGFL6受体的其他信息知之甚少。我们评估了可能的EGFL6受体，发现EGFL6治疗卵巢癌细胞会导致EGFR的短暂磷酸化和HER2和HER3的延长磷酸化以及随后的ERK （pERK）磷酸化。我们发现EGFL6直接结合HER3。然而，EGFL6驱动的HER3的延长激活依赖于完整的EGFL6整合素结合RGD结构域。免疫沉淀和接近结扎实验证实，EGFL6对癌细胞的处理可诱导her2 /3-整合素-β3异质复合物。EGFL6在EGFR/HER受体抑制剂耐药细胞中上调，EGFL6治疗增加了体外对EGFR/HER抑制剂的耐药性，这表明EGFL6可能在HER靶向治疗的耐药中发挥作用。有趣的是，我们发现，在egfl6处理的有丝分裂的卵巢癌细胞中，pERK定位于中心体。egfl6中和抗体和HER蛋白靶向抑制剂都导致pERK中心体定位异常，并伴有有丝分裂纺锤体排列改变和有丝分裂突变。此外，与单独治疗相比，抗egfl6与泛egfr受体抑制剂neratinib联合治疗在体外导致异常pERK定位和癌细胞死亡增加，并在体内显著限制肿瘤生长。综上所述，我们的数据表明，EGFL6是HER3的新配体，通过改变pERK定位，双重靶向EGFL6/HER信号轴可能是卵巢癌的有效治疗策略。意义：这项工作揭示了EGFL6是一种以前未被识别的HER3配体，它可以增加对HER家族靶向治疗的耐药性。我们还揭示了pERK在有丝分裂中位于中心体ph3下游的新功能。重要的是，我们发现EGFL6是提高EGFR/ her靶向治疗疗效的重要治疗靶点。

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引用次数: 0