UHRF1

ROCKVILLE, Md. and SUZHOU, China, April 7, 2024 /PRNewswire/ -- Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancer, age-related diseases, and chronic hepatitis B (CHB), announced today that it releases the latest results from three preclinical studies of its novel drug candidates olverembatinib, MDM2-p53 inhibitor alrizomadlin (R&D Code: APG-115), FAK/ALK/ROS1 tyrosine kinase inhibitor APG-2449, and embryonic ectoderm development (EED) inhibitor APG-5918, at the 2024 American Association of Cancer Research Annual Meeting (AACR 2024). This year's AACR annual meeting will be held from April 5-10 2024, in San Diego, California, USA. "We are pleased to present the preclinical research data of four assets in our pipeline at the AACR 2024. The results provided essential support for the potential clinical development and therapeutic combinations of these compounds in SDH-deficient neoplasms, prostate cancer, and ovarian cancer," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "Moving forward, we will continue to advance these programs toward the clinical stage in order to bring more treatment options to patients in need." The details of these three preclinical studies are as follows: Olverembatinib, a novel multikinase inhibitor, demonstrates superior antitumor activity in succinate dehydrogenase (SDH)-deficient neoplasms Abstract#: 1971 Time: Monday April 8, 2024, 9:00 AM - 12:30 PM (Pacific Time) Introduction: Succinate dehydrogenase (SDH) – deficient (dSDH) neoplasms are identified by the loss of immunohistochemical expression of SDHB due to the bi-allelic inactivation of any of the four components of mitochondrial SDH complex (SDH A-D). Succinate accumulation, due to SDH deficiency, is involved in tumorigenesis of different types of cancers including gastrointestinal stromal tumor (GIST), paraganglioma, pheochromocytoma, renal cell carcinoma, pituitary adenomas, and pancreatic neuroendocrine tumors. The prognosis of patients with dSDH neoplasia, especially GIST, is poor and approved tyrosine kinase inhibitors (TKIs) have limited efficacy. There is a high unmet medical need for these patients. Olverembatinib, a novel multi-kinase inhibitor, targets a broad spectrum of kinases and has demonstrated promising efficacy in dSDH GIST patients in an ongoing phase I clinical trial. In this study, we assessed antitumor effects of olverembatinib in preclinical models of dSDH cancers and dSDH GIST primary tumor cells, and explored potential mechanisms of action. Conclusions: Olverembatinib showed superior anti-tumor activity in dSDH cell lines in vitro and human dSDH GIST primary tumor cells ex vivo. Olverembatinib, as a multi-target kinase inhibitor, exerted antitumor effects by modulating multiple signaling pathways including hypoxia, angiogenesis, apoptosis, proliferation, and survival, which are involved in tumorigenesis of dSDH cancers. Olverembatinib demonstrated more potent in vivo antitumor activity in mice bearing PC12#5F7 (SDHB KD) xenograft tumors than other TKIs. Western blot analysis in tumor tissues collected from mice further confirmed the modulation of the signal pathways by olverembatinib observed in cell lines. In summary, the results provide a rationale for future clinical development of olverembatinib in dSDH cancers. Embryonic ectoderm development (EED) inhibitor APG-5918 (EEDi-5273) and MDM2 inhibitor alrizomadlin (APG-115) synergistically inhibit tumor growth in preclinical models of prostate cancer (PCa) Abstract#: 3223 Time: Monday April 8, 2024, 1:30 PM - 5:00 PM (Pacific Time) Introduction: Prostate cancer (PCa) is one of the most frequently diagnosed malignancies among elderly males. Androgen deprivation therapy (ADT) with or without androgen receptor (AR) inhibitors is widely used as initial treatment for advanced PCa. However, most ADT-treated patients eventually develop castration-resistant prostate cancer (CRPC), which is in urgent need of novel therapies. Polycomb repressive complexes 2 (PRC2) dysregulation is common in PCa and correlates with poor prognosis. PRC2 mediates histone H3 lysine 27 tri-methylation (H3K27me3), a repressive epigenetic marker for gene transcription. embryonic ectoderm development (EED), a PRC2 core component, is crucial for histone methyltransferase activity through direct binding to H3K27me3. MDM2, a negative regulator of the tumor suppressor p53, is frequently amplified or overexpressed in PCa, and associated with poor clinical outcomes and metastasis. The aim of this study was to evaluate antitumor activity and molecular mechanisms of the investigational, clinical-stage EED inhibitor APG-5918/EEDi-5273 and MDM2 selective inhibitor alrizomadlin (APG-115) in PCa preclinical models Conclusions: In PCa preclinical models, the combination of APG-5918 and alrizomadlin synergistically inhibited cellular proliferation and induced cellular apoptosis. APG-5918 in combination with alrizomadlin synergistically enhanced antitumor activity in PCa xenograft models in vivo. Mechanistically, PD analysis revealed that APG-5918 downregulated the oncogenic DNA methylation factors (UHRF1, DNMT1) and histone methylation marker H3K27me3. Alrizomadlin markedly downregulated UHRF1 and DNMT1, and upregulated p53 and p21 expression. Combined treatment further enhanced downregulation of DNMT1, UHRF1, cell cycle pathway proteins (pRb, CDK6), antiapoptotic protein MCL-1, and synergistically increased cleavage of PARP-1, a marker of apoptosis. Therefore, the findings provide a scientific rationale for future clinical development of APG-5918 and alrizomadlin to treat patients with PCa. APG-2449, a novel focal adhesion kinase (FAK) inhibitor, inhibits metastasis and enhances the antitumor efficacy of PEGylated liposome doxorubicin (PLD) in epithelial ovarian cancer (EOC) Abstract#: 4569 Time: Tuesday April 9, 2024, 9:00 AM - 12:30 PM (Pacific Time) Introduction: Ovarian cancer is among the leading causes of cancer-related death in women, and most cases are diagnosed at later stages with distant metastasis. FAK overexpression or activation occurs in a substantial proportion of epithelial ovarian cancers (EOCs) and is predictive of poor clinical outcomes. FAK plays an important role in cell migration and chemoresistance, rendering FAK inhibition a promising treatment approach to reduce metastasis of tumor cells and sensitize them to chemotherapy. FAK is therefore emerging as a potential treatment target. The aim of this study was to evaluate the antitumor efficacy of investigational APG-2449, a novel FAK inhibitor, combined with PLD, a commonly used chemotherapy, in relapsed or refractory ovarian cancer. Conclusions: APG-2449 combined with doxorubicin showed synergistic antiproliferative effects in both platinum-resistant and platinum-sensitive ovarian cancer cell lines. FAK inhibition via APG-2449 alone attenuated migration of ovarian cancer cells in a dose-dependent manner. APG-2449 in combination with PLD showed enhanced antitumor activity in platinum-resistant OVCAR-3 ovarian cancer CDX model. The combination regimen prolonged ascites-free and survival times in the ID8-Luc peritoneal syngeneic model. These promising results support the future clinical development of this combination treatment for ovarian cancer. About Ascentage Pharma Ascentage Pharma (6855.HK) is a globally focused biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B, and age-related diseases. On October 28, 2019, Ascentage Pharma was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code 6855.HK. Ascentage Pharma focuses on developing therapeutics that inhibit protein-protein interactions to restore apoptosis, or programmed cell death. The company has built a pipeline of 9 clinical drug candidates, including novel, highly potent Bcl-2, and dual Bcl-2/Bcl-xL inhibitors, as well as candidates aimed at IAP and MDM2-p53 pathways, and next-generation tyrosine kinase inhibitors (TKIs). Ascentage Pharma is also the only company in the world with active clinical programs targeting all three known classes of key apoptosis regulators. The company is conducting more than 40 Phase I/II clinical trials in the US, Australia, Europe, and China. Ascentage Pharma has been designated for multiple Major National R&D Projects, including five Major New Drug Projects, one New Drug Incubator status, four Innovative Drug Programs, and one Major Project for the Prevention and Treatment of Infectious Diseases. Olverembatinib, the company's core drug candidate developed for the treatment of drug-resistant chronic myeloid leukemia (CML) and the company's first approved product, has been granted Priority Review Designations and Breakthrough Therapy Designations by the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA). To date, the drug had been included into the China 2022 National Reimbursement Drug List (NRDL). Furthermore, olverembatinib has been granted an Orphan Drug Designation (ODD) and a Fast Track Designation (FTD) by the US FDA, and an Orphan Designation by the EMA of the EU. To date, Ascentage Pharma has obtained a total of 16 ODDs from the US FDA and 1 Orphan Designation from the EMA of the EU for 4 of the company's investigational drug candidates. Leveraging its robust R&D capabilities, Ascentage Pharma has built a portfolio of global intellectual property rights and entered into global partnerships with numerous renowned biotechnology and pharmaceutical companies and research institutes such as UNITY Biotechnology, MD Anderson Cancer Center, Mayo Clinic, Dana-Farber Cancer Institute, MSD, and AstraZeneca. The company has built a talented team with global experience in the discovery and development of innovative drugs and is setting up its world-class commercial manufacturing and Sales & Marketing teams. One pivotal aim of Ascentage Pharma is to continuously strengthen its R&D capabilities and accelerate its clinical development programs, in order to fulfil its mission of addressing unmet clinical needs in China and around the world for the benefit of more patients. Forward-Looking Statements The forward-looking statements made in this article relate only to the events or information as of the date on which the statements are made in this article. Except as required by law, Ascentage Pharma undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events, or otherwise, after the date on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. In this article, statements of, or references to, our intentions or those of any of our Directors or our Company are made as of the date of this article. Any of these intentions may alter in light of future development. SOURCE Ascentage Pharma

以营养干预手段来抗癌，最近几年还真吸引到了不少关注，比如热量限制或生酮饮食，可能让癌细胞因为断掉关键营养物被“饿死”，还有一些营养干预策略则能从不同角度，对抗肿瘤免疫应答起到调 以营养干预手段来抗癌，最近几年还真吸引到了不少关注，比如热量限制或生酮饮食，可能让癌细胞因为断掉关键营养物被“饿死”，还有一些营养干预策略则能从不同角度，对抗肿瘤免疫应答起到调节作用。 近期，同济大学附属上海市第十人民医院王平教授团队在Cancer Cell上发表的一项最新研究，就揭示了以甲硫氨酸限制（MR）作为营养干预策略，助力抗癌的表观遗传策略：MR可通过影响环鸟苷酸-腺苷酸合成酶（cGAS）甲基化，增强cGAS调控的抗肿瘤免疫应答，实现对放疗和免疫治疗的增效[1]。 论文首页截图 科学界对MR作用的研究从上世纪90年代就开始了，在证实MR可以延长多种动物乃至人类的寿命后，科研探索又逐渐拓宽到其它领域，抗癌当然也不例外[2-3]。既往研究认为，甲硫氨酸可参与对癌细胞意义重大的细胞内甲基化反应，因此许多癌细胞存在“甲硫氨酸依赖性”，MR就会让它们非常难熬[4]。 而此次王平教授团队研究的切入点，则是探索限制甲硫氨酸对cGAS甲基化水平和活性是否会有影响，毕竟cGAS-STING通路对抗肿瘤免疫应答有着深远的影响，借助甲硫氨酸精准调节cGAS，也许会解锁许多全新的可能性。 研究者们首先评估了各种氨基酸对cGAS-STING通路活性的影响，在全氨基酸缺乏的培养基中，癌细胞内的cGAS-STING通路激活水平更高，而只有专门补充甲硫氨酸，才能通过限制cGAS的活性，抑制cGAS-STING通路激活。 甲硫氨酸对cGAS-STING通路活性的影响 限制甲硫氨酸的作用也很快被证实：对小鼠喂食MR饮食可有效增强放疗对野生型肿瘤的杀伤力，但这种增效对Cgas缺陷型肿瘤不成立，且MR饮食还可改善CD4/CD8阳性T细胞，以及树突状细胞、巨噬细胞等关键免疫细胞对肿瘤的浸润。 限制甲硫氨酸饮食可改善放疗效果 进一步实验显示，限制甲硫氨酸摄入可显著降低癌细胞内的S-腺苷甲硫氨酸（SAM）水平，而SAM调节的cGAS关键位点（hK362和mK350）甲基化，则可通过促进UHRF1依赖性的cGAS染色质栓系（chromatin tethering），对cGAS活性起调控作用，主要负责催化这一过程的则是组蛋白甲基化酶SUV39H1。 换句话说，抑制甲硫氨酸摄取或抑制SUV39H1活性，就能降低cGAS的甲基化修饰，使它脱离染色质束缚并进入细胞质，这样就能增强抗肿瘤免疫应答，实验显示在敲除SUV39H1或Cgas表达后，小鼠体内的肿瘤生长明显更慢，免疫细胞浸润状态有所改善，放疗和PD-1抑制剂的抑癌作用也更为显著。 敲除SUV39H1或Cgas实现的协同增效 来自癌症基因组图谱计划（TCGA）等数据库的资料则显示，SUV39H1在多种实体肿瘤中存在高表达，且与患者生存和肿瘤免疫细胞浸润呈负相关，肿瘤组织内还同时存在cGAS的高度甲基化，意味着cGAS无法脱离束缚、增强抗肿瘤免疫，cGAS甲基化水平较高也与结直肠癌患者的不良预后有关。 cGAS甲基化升高与肠癌患者预后不良有关 值得一提的是，研究团队还发现在结直肠癌中，cGAS甲基化水平与KRAS/NRAS基因共突变，以及错配修复蛋白（MMR）和微卫星不稳定性（MSI）水平相关，特别是cGAS甲基化水平较低与MSI-H高度相关，而MSI-H是当前肠癌免疫治疗的重要标志物，因此靶向cGAS再联合免疫治疗和放疗，很可能会打出“暴击”。 当然了，到底应该如何安全、顺利地限制癌症患者的甲硫氨酸摄入，或是开发靶向SUV39H1或Cgas的药物，还需要开展许多探索，但本次研究确实提出了全新的治疗可能性，期待后续的转化研究吧。 以营养干预手段来抗癌，最近几年还真吸引到了不少关注，比如热量限制或生酮饮食，可能让癌细胞因为断掉关键营养物被“饿死”，还有一些营养干预策略则能从不同角度，对抗肿瘤免疫应答起到调节作用。 近期，同济大学附属上海市第十人民医院王平教授团队在Cancer Cell上发表的一项最新研究，就揭示了以甲硫氨酸限制（MR）作为营养干预策略，助力抗癌的表观遗传策略：MR可通过影响环鸟苷酸-腺苷酸合成酶（cGAS）甲基化，增强cGAS调控的抗肿瘤免疫应答，实现对放疗和免疫治疗的增效[1]。 论文首页截图 科学界对MR作用的研究从上世纪90年代就开始了，在证实MR可以延长多种动物乃至人类的寿命后，科研探索又逐渐拓宽到其它领域，抗癌当然也不例外[2-3]。既往研究认为，甲硫氨酸可参与对癌细胞意义重大的细胞内甲基化反应，因此许多癌细胞存在“甲硫氨酸依赖性”，MR就会让它们非常难熬[4]。 而此次王平教授团队研究的切入点，则是探索限制甲硫氨酸对cGAS甲基化水平和活性是否会有影响，毕竟cGAS-STING通路对抗肿瘤免疫应答有着深远的影响，借助甲硫氨酸精准调节cGAS，也许会解锁许多全新的可能性。 研究者们首先评估了各种氨基酸对cGAS-STING通路活性的影响，在全氨基酸缺乏的培养基中，癌细胞内的cGAS-STING通路激活水平更高，而只有专门补充甲硫氨酸，才能通过限制cGAS的活性，抑制cGAS-STING通路激活。 甲硫氨酸对cGAS-STING通路活性的影响 限制甲硫氨酸的作用也很快被证实：对小鼠喂食MR饮食可有效增强放疗对野生型肿瘤的杀伤力，但这种增效对Cgas缺陷型肿瘤不成立，且MR饮食还可改善CD4/CD8阳性T细胞，以及树突状细胞、巨噬细胞等关键免疫细胞对肿瘤的浸润。 限制甲硫氨酸饮食可改善放疗效果 进一步实验显示，限制甲硫氨酸摄入可显著降低癌细胞内的S-腺苷甲硫氨酸（SAM）水平，而SAM调节的cGAS关键位点（hK362和mK350）甲基化，则可通过促进UHRF1依赖性的cGAS染色质栓系（chromatin tethering），对cGAS活性起调控作用，主要负责催化这一过程的则是组蛋白甲基化酶SUV39H1。 换句话说，抑制甲硫氨酸摄取或抑制SUV39H1活性，就能降低cGAS的甲基化修饰，使它脱离染色质束缚并进入细胞质，这样就能增强抗肿瘤免疫应答，实验显示在敲除SUV39H1或Cgas表达后，小鼠体内的肿瘤生长明显更慢，免疫细胞浸润状态有所改善，放疗和PD-1抑制剂的抑癌作用也更为显著。 敲除SUV39H1或Cgas实现的协同增效 来自癌症基因组图谱计划（TCGA）等数据库的资料则显示，SUV39H1在多种实体肿瘤中存在高表达，且与患者生存和肿瘤免疫细胞浸润呈负相关，肿瘤组织内还同时存在cGAS的高度甲基化，意味着cGAS无法脱离束缚、增强抗肿瘤免疫，cGAS甲基化水平较高也与结直肠癌患者的不良预后有关。 cGAS甲基化升高与肠癌患者预后不良有关 值得一提的是，研究团队还发现在结直肠癌中，cGAS甲基化水平与KRAS/NRAS基因共突变，以及错配修复蛋白（MMR）和微卫星不稳定性（MSI）水平相关，特别是cGAS甲基化水平较低与MSI-H高度相关，而MSI-H是当前肠癌免疫治疗的重要标志物，因此靶向cGAS再联合免疫治疗和放疗，很可能会打出“暴击”。 当然了，到底应该如何安全、顺利地限制癌症患者的甲硫氨酸摄入，或是开发靶向SUV39H1或Cgas的药物，还需要开展许多探索，但本次研究确实提出了全新的治疗可能性，期待后续的转化研究吧。

导读：KRAS是肺癌的一个常见驱动因素。为了确定KRAS在肺癌中的特异性弱点，我们对来自Kras突变小鼠肺癌模型的原生球体进行了RNAi筛选，并发现了一个表观遗传调节器含有PHD和RING指域的类生物素1（Ubiquitin-like containing PHD and RING finger domains 1UHRF1）。在人类肺癌模型中，UHRF1被敲除后会选择性地损害生长，并只在KRAS突变细胞中诱导凋亡。对UHRF1剔除的KRAS突变体细胞进行全基因组甲基化和基因表达分析，发现全局DNA低甲基化导致肿瘤抑制基因（TSG）的上调。7月5日，来自加州大学的研究团队在《Nature Communications》上发表了名为“UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma”的文章，研究发现UHRF1在KRAS驱动的肿瘤发生中起着关键作用，可能是治疗KRAS突变的NSCLC和/或其他KRAS驱动的癌症的一个有吸引力的药物靶点。https://www.nature.com/articles/s41467-023-39591-2研究背景 01 肺癌是世界上癌症相关死亡的主要原因，大约30%的非小细胞肺癌（NSCLC）病例是由致癌的KRAS1驱动的。最近，针对特定KRAS等位基因的小分子药物的开发以及在NSCLC患者中使用这些药物的临床试验结果，重新激发了人们对直接抑制KRAS的兴趣。然而，直接靶向KRAS目前只对一部分患者可行。此外，大多数患者对直接KRAS抑制产生内在和获得性耐药性，这表明需要继续补充新方法来抑制KRAS驱动的肿瘤发生针对KRAS驱动的癌症的另一个途径是利用致癌基因的特定弱点。虽然全基因组RNAi或CRISPR/Cas9筛选已被广泛用于寻找KRAS特异性依赖，但这些筛选大多局限于在标准的二维（2D）环境下培养的成熟细胞系，可能会错过在其他生长条件下出现的漏洞。相比之下，三维（3D）培养物再现了体内肿瘤的更多特征，因此可能是研究癌症生物学的一个更好的模型。此外，三维培养物已被发现富含肿瘤繁殖细胞（TPCs），这是驱动肿瘤发生、维持和发展的一个细胞亚群。虽然在3D中使用原代肿瘤细胞的功能基因组筛选在技术上具有挑战性，而且产量有限，但我们推断这样的筛选策略可能具有独特的潜力，可以发现在2D筛选中没有观察到的与致癌性KRAS驱动的癌症有关的新依赖性。因此，我们在三维培养的原生细胞中进行了RNAi筛选，这些细胞来自于Kras激活和p53缺失驱动的肺癌基因工程小鼠模型（GEMM）。与正常组织相比，UHRF1是在许多人类癌症中高度表达的E3泛素连接酶，并与疾病的快速发展有关。UHRF1在细胞周期S期由DNA甲基转移酶1（DNMT1）介导的半甲基化DNA的甲基化中的作用最为突出。UHRF1也被认为是在结直肠癌的整个细胞周期中维持DNA甲基化的必要条件。研究过程 02 我们利用基因工程小鼠模型、来自这些模型的原发性肿瘤细胞的功能缺失RNAi筛选，以及人类非小细胞肺癌细胞系的三维培养，表明UHRF1在KRAS驱动的致癌过程中发挥关键作用。在体外，在NSCLC的小鼠和人类模型中，UHRF1基因敲除抑制了3D生长并导致细胞凋亡。在肺癌的GEM模型中，UHRF1的缺失导致肿瘤数量和肿瘤大小减少，并明显延长生存期，即使是在由Kras激活和p53缺失驱动的高侵略性模型中。事实上，在这些小鼠中，我们无法检测到UHRF1完全丧失的任何肿瘤，这表明UHRF1的表达对肿瘤的发展很重要。在带有KRAS突变的肺癌患者中，UHRF1的高表达与肿瘤抑制基因的表达反相关，并预示着患者的不良生存率。总之，我们的数据表明，UHRF1通过诱导TSG启动子区域的高甲基化导致其表达减少，从而有助于KRAS驱动的肿瘤发生。我们发现至少有80个肺癌特异性TSG受到UHRF1的调节。其中许多TSG是WNT/β-catenin途径的抑制剂或参与激活凋亡的基因。虽然UHRF1驱动的这些TSG的有限子集在体外的肺癌细胞系中已经被证实，但在这里我们证明UHRF1对TSG的表达有更广泛的影响。我们假设，这种对大量TSG的广泛影响是UHRF1在肺癌中发挥作用的原因。甲基化驱动的致瘤表型在结肠直肠癌（CRC）中得到了最好的描述，先前的研究也表明，UHRF1在CRC中起到了介导这些效应的作用。独立地讲，KRAS也被证明在体外驱动CRC细胞的TSG启动子高甲基化。总的来说，我们的结果表明，肺癌中受UHRF1调控的TSG与CRC中被认为受UHRF1调控的TSG不重叠，可能是由于组织特异性的影响。UHRF1和KRAS之间的机制联系仍有待完全了解。以前，UHRF1被预测为肺癌中KRAS的转录靶点，使用丰富的调节子分析（VIPER）虚拟推断蛋白活性。最近的一项研究，使用VIPER和CRISPR筛选的组合，也发现UHRF1是胰腺癌中最重要的基因之一，表明这种主要由KRAS驱动的癌症对UHRF1有特别的依赖性。在胰腺癌的小鼠模型中，Kras G12D的过度表达被证明可以诱导Uhrf1的表达，而在人类胰腺导管腺癌（ PDAC ）细胞系中，KRAS的敲除降低了UHRF1的蛋白水平。与这些结果一致，我们显示KRAS敲除导致人类KRAS突变的肺癌细胞系中UHRF1 mRNA和蛋白表达减少。然而，伴随着环蛋白B1和D1的减少以及流式细胞仪的细胞周期分析，表明这些细胞处于G1期。UHRF1的表达以前被证明是依赖于细胞周期的，并在S和G2期达到峰值，因此，UHRF1蛋白的损失可能是细胞周期停滞在G1期的结果，而不是KRAS耗竭的直接后果。与这一假设一致，我们观察到在瞬时表达致癌KRAS后，KRAS野生型细胞系的UHRF1蛋白水平没有增加。此外，UHRF1的表达被证明是由叉头盒家族转录因子（FOXM1）和细胞周期相关转录因子1（E2F1）驱动的，这两者都是受细胞周期调节。值得注意的是，UHRF1本身的缺失也被证明会影响细胞周期的进展，我们观察到的UHRF1敲除导致DNA损伤水平的增加和细胞在S期的积累也支持了这一点。这种影响在KRAS突变型NSCLC细胞中也比在KRAS野生型NSCLC细胞中更明显，这表明前者可能对未解决的DNA双链断裂在S期的积累更敏感。虽然UHRF1的表达一般被认为是以细胞周期依赖性的方式调节的，但KP小鼠肺部肿瘤的免疫荧光成像显示Uhrf1存在于细胞周期的不同阶段，包括G1和G0，这表明其在肺癌中的细胞周期依赖性表达被解除。因此，我们假设UHRF1被突变的KRAS调控至少是部分独立于细胞周期的。然而，UHRF1的这种表达改变的确切机制将需要进一步调查。我们发现两个肺部细胞系之间受KRAS敲除的差异性甲基化几乎没有重叠，同时注意到与对照组细胞相比，双核甘酸(CpG)甲基化的变异性明显增加。作者还证明，由KRAS驱动的甲基化变化是独立于典型的丝裂原活化蛋白激酶(MAPK)信号的，指向了其他效应因子。我们的观察表明，在肺癌中，UHRF1可能是KRAS的一个潜在效应器，介导其在DNA甲基化的作用。先前的研究表明，在RAS驱动的癌症的临床前模型中，将抑制表观遗传调节器与抑制MAPK激酶(MEK) 或磷脂酰肌醇3-激酶(PI3K)相结合是有效的，支持表观遗传调节器可能有助于KRAS驱动的致癌的一般概念。与此一致，我们在此表明，UHRF1的基因消融与KRAS G12C、MEK或PI3K的药物抑制相结合，在体外KRAS突变的肺癌细胞中产生协同抗增殖作用。因此，我们的工作表明，共同针对UHRF1和KRAS可能构成一种可行的治疗KRAS突变癌症的方法。研究结论 03 结果表明，UHRF1在KRAS驱动的肿瘤发生中起着关键作用，可能是治疗KRAS突变的NSCLC和/或其他KRAS驱动的癌症的一个有吸引力的药物靶点。参考资料：https://www.nature.com/articles/s41467-023-39591-2