作者: Wang, Le ; Li, Qin-Ying ; Yu, Xu ; Xu, Li ; Liang, Yi-Zhong ; Xie, Qi ; Gong, Zhou ; Wang, Ming ; Zhang, Cong ; Ma, Li-Yun ; Wu, Xiao-Wei ; Zhao, Jing ; Jiang, Ming ; Zheng, Si-Yang

Extracellular vesicles (EVs) have garnered significant attention in biomedical applications. However, the rapid, efficient, and unbiased separation of EVs from complex biological fluids remains a challenge due to their heterogeneity and low abundance in biofluids. Herein, we report a novel approach to reconfigure and modify an artificial insertion peptide for the unbiased and rapid isolation of EVs in 20 min with ∼80% recovery in neutral conditions. Moreover, the approach demonstrates exceptional anti-interference capability and achieves a high purity of EVs comparable to standard ultracentrifugation and other methods. Importantly, the isolated EVs could be directly applied for downstream protein and nucleic acid analyses, including proteomics analysis, exome sequencing analysis, as well as the detection of both epidermal growth factor receptor (EGFR) and V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) gene mutation in clinical plasma samples. Our approach offers great possibilities for utilizing EVs in liquid biopsy, as well as in various other biomedical applications.

2024-12-01·Molecular Biology Reports

The RAS oncogene in brain tumors and the involvement of let-7 microRNA

Review

作者: Messina, Samantha

AbstractRAS oncogenes are master regulator genes in many cancers. In general, RAS-driven cancers have an oncogenic RAS mutation that promotes disease progression (colon, lung, pancreas). In contrast, brain tumors are not necessarily RAS-driven cancers because RAS mutations are rarely observed. In particular, glioblastomas (the most lethal brain tumor) do not appear to have dominant genetic mutations that are suitable for targeted therapy. Standard treatment for most brain tumors continues to focus on maximal surgical resection, radiotherapy and chemotherapy. Yet the convergence of genomic aberrations such as EGFR, PDGFR and NF1 (some of which are clinically effective) with activation of the RAS/MAPK cascade is still considered a key point in gliomagenesis, and KRAS is undoubtedly a driving gene in gliomagenesis in mice. In cancer, microRNAs (miRNA) are small, non-coding RNAs that regulate carcinogenesis. However, the functional consequences of aberrant miRNA expression in cancer are still poorly understood. let-7 encodes an intergenic miRNA that is classified as a tumour suppressor, at least in lung cancer. Let-7 suppresses a plethora of oncogenes such as RAS, HMGA, c-Myc, cyclin-D and thus suppresses cancer development, differentiation and progression. let-7 family members are direct regulators of certain RAS family genes by binding to the sequences in their 3′untranslated region (3′UTR). let-7 miRNA is involved in the malignant behaviour in vitro—proliferation, migration and invasion—of gliomas and stem-like glioma cells as well as in vivo models of glioblastoma multiforme (GBM) via KRAS inhibition. It also increases resistance to certain chemotherapeutic agents and radiotherapy in GBM. Although let-7 therapy is not yet established, this review updates the current state of knowledge on the contribution of miRNA let-7 in interaction with KRAS to the oncogenesis of brain tumours.

2024-12-01·Bioorganic Chemistry

Design, synthesis, and evaluation of dual son of sevenless 1 (SOS1) and epidermal growth factor receptor (EGFR) inhibitors for the treatment of cancers

Article

作者: Huang, Chenyang ; Zeng, Yi ; Wu, Xiaoxing ; Hou, Qiangqiang ; Cheng, Jiaqi ; Jiang, Wenhua

The treatment of KRAS mutant tumors remains challenging and dual-targeted small-molecule drugs are considered to be innovative therapeutic alternatives. Herein, we discovered a series of SOS1 and EGFR dual inhibitors by employing a fused pharmacophore strategy and structural optimization. Notably, compound 4 exhibited potent SOS1 (IC₅₀ = 8.3 nM) and EGFR (IC₅₀ = 14.6 nM) inhibitory activities and markedly inhibited the proliferation of other KRAS-mutant cancer cell lines. Furthermore, Western blot analysis confirmed that compound 4 effectively reduced the level of downstream p-ERK. These results indicated that compound 4 could serve as a potential compound for treating KRAS mutant tumors.

985

项与 EGFR x KRAS 相关的新闻（医药）

2024-10-30

·PRNewswire

LUNGevity Foundation and Living Beyond Breast Cancer Partner to Bring the No One Missed Campaign to the Breast Cancer Community

The collaborative effort drives awareness about biomarker testing to the metastatic breast cancer community WASHINGTON, Oct. 30, 2024 /PRNewswire/ -- LUNGevity Foundation, a nationally recognized nonprofit dedicated to transforming how people are diagnosed and live with lung cancer through research, education, and support, is proud to announce a partnership with Living Beyond Breast Cancer (LBBC), a nationally recognized nonprofit dedicated to providing trusted information for people at every stage of their breast cancer journey, to spread awareness about biomarker testing for people diagnosed with metastatic breast cancer through the No One Missed: Breast Cancer campaign. The successful No One Missed: Lung Cancer campaign launched in 2021 and has reached millions of people with the importance of biomarker testing – specific drivers in a person's cancer that cause the cancer to grow and spread in different ways – at diagnosis and progression. With the support of campaign founding partner AstraZeneca and additional sponsors, the No One Missed: Breast Cancer campaign launched in June and is rapidly reaching a new audience. As with lung cancer, biomarker testing is a powerful tool that plays a critical role in understanding and guiding treatment decisions for those living with metastatic breast cancer (MBC). However, not all patients with MBC receive biomarker testing at the time of diagnosis and when there is cancer progression. There is no cure for MBC despite clinical advancements, with one-third of women diagnosed in the US living at least 5 years after diagnosis. However, knowing the presence of biomarkers can help those living with MBC and their healthcare teams make better treatment decisions. "As the understanding of metastatic breast cancer grows and more treatment options become available, biomarker testing has become a game changer to help patients and their doctors make more informed decisions," said Jean Sachs, MSS, MLSP, Chief Executive Officer, Living Beyond Breast Cancer. "For someone living with metastatic breast cancer, their cancer may evolve and their biomarkers may change. This signifies an important need for conversations between patients and healthcare teams about biomarker testing at diagnosis and every time a cancer progresses." "LUNGevity is proud to partner with Living Beyond Breast Cancer to expand the reach of the No One Missed campaign," said Andrea Ferris, president and CEO, LUNGevity Foundation. "We hope this resource will help improve patient and doctor conversations about biomarker testing." "In the US, 1 in 8 women will be diagnosed with breast cancer in their lifetime," said Mohit Manrao, Senior Vice President, US Oncology Business Unit, AstraZeneca. "We're proud to partner with organizations like LUNGevity Foundation and Living Beyond Breast Cancer to change these numbers and ensure patients have access to critical resources and information to better understand the unique qualities of their cancer, and ultimately ensure they receive the right treatment at the right time." About the No One Missed Campaign No One Missed is a community-led campaign driven by LUNGevity Foundation and supported by patient advocacy, pharmaceutical, and biotechnology organizations. The campaign's mission is to build public awareness of biomarker testing as a critical part of a cancer diagnosis and prognosis and empower patients to discuss biomarker testing with their healthcare team. No One Missed: Lung Cancer is supported by founding partner AstraZeneca, supporting member Daiichi-Sankyo, members Merck and Regeneron, and supporters Boehringer Ingelheim, Foundation Medicine, Genentech, Pfizer, Taiho Oncology, Takeda Oncology, and Thermo Fisher Scientific. Supporting partners include AONN, ALK Positive, AEACap, EGFR Resisters, Exon20Group, IASLC, KRAS Kickers, MET Crusaders, NTRKers, ONS, RETpositive, The ROS1ders, and US Oncology Research. No One Missed: Breast Cancer is supported by premier sponsor AstraZeneca; member sponsors Daiichi-Sankyo, Lilly, Merck, and Genentech; supporter sponsor Novartis; and friend sponsors Foundation Medicine and Relay Therapeutics. Additionally, No One Missed: Breast Cancer is supported by partners Breastcancer.org, Cancer Support Community, FORCE, Metastatic Breast Cancer Alliance, SHARE, Susan G. Komen, The Chrysalis Initiative, TOUCH: The Black Breast Cancer Alliance, and Young Survival Coalition. About Living Beyond Breast Cancer Living Beyond Breast Cancer is a national nonprofit organization that seeks to create a world that understands there is more than one way to have breast cancer. To fulfill its mission of providing trusted information and a community of support to those impacted by the disease, Living Beyond Breast Cancer offers in-person experiences and on-demand emotional, practical, and evidence-based content that is meaningful to those newly diagnosed, in-treatment, post-treatment and living with metastatic disease. Visit for more information. About LUNGevity Foundation LUNGevity, the nation's leading lung cancer organization, is transforming what it means to be diagnosed and live with lung cancer. LUNGevity seeks to make an immediate impact on quality of life and survivorship for everyone touched by the disease—while promoting health equity by addressing disparities throughout the care continuum. Through research, we use an innovative and holistic approach to finding lung cancer earlier when it is most treatable; advance research into new treatments so people may live longer and better; and ensure a diverse, vital pipeline of investigators for the future of the lung cancer field. Through advocacy, we foster groundbreaking collaborations to ensure all people have access to screening, biomarker testing, and treatment breakthroughs. Through community, we educate, support, and connect people affected by lung cancer so that they can get the best healthcare and live longer and better lives. Comprehensive resources include a medically vetted and patient-centric website, Patient Gateways for specific types of lung cancer, a toll-free HELPLine for personalized support, international survivor conferences, and tools to find a clinical trial. All these programs are designed to help us achieve our vision—a world where no one dies of lung cancer. LUNGevity Foundation is proud to be a four-star Charity Navigator organization. Please visit to learn more. SOURCE LUNGevity Foundation WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

2024-10-25

·摩熵医药

2024年非小细胞肺癌（NSCLC）罕见突变靶向治疗及市场竞争格局！

注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需要得到授权。非小细胞肺癌（NSCLC）是全球癌症死亡的主要原因之一，其治疗方案的探索与革新始终是全球医疗领域关注的焦点。随着精准医疗时代的到来，针对特定基因突变的靶向疗法以及免疫疗法的兴起，为NSCLC患者带来了前所未有的治疗希望。除了EGFR和ALK之外，NSCLC还有许多不常见但仍然重要的分子亚型，包括ROS1融合、MET外显子14跳跃突变、RET融合、NTRK融合和BRAF V600E突变等。本文基于摩熵咨询最新发布的《市场研究专题报告——非小细胞肺癌药物》部分精彩内容，旨在深入探讨BRAF/NTRK/MET/RET等少见靶点突变非小细胞肺癌（NSCLC）的诊疗指南及靶向药物的最新进展，以期为相关领域的研究者、临床医生及政策制定者提供有价值的参考。 01 ROS1融合阳性NSCLC靶向治疗 ROS1基因（c-ROS 肉瘤致癌因子-受体酪氨酸激酶），与 EGFR、ALK 均为非小细胞肺癌（NSCLC）明确的驱动基因，属于酪氨酸激酶胰岛素受体基因。ROS1基因发生致癌变异，会激活其下游通路的信号，造成细胞过度地生长及增殖，驱动肿瘤的发生。变异类型包括融合（重排）、点突变、扩增，其中融合是ROS1 基因主要变异类型。 ROS1融合在NSCLC中约为1%，主要发生在年轻（中位年龄50岁）、不吸烟的肺腺癌患者中。目前，在国内获批上市的ROS1抑制剂有4款：克唑替尼、恩曲替尼、富马酸安奈克替尼胶囊和第二代NTRK/ROS1抑制剂瑞普替尼，迈入全新“四足鼎立”时代。辉瑞的克唑替尼是一种ALK/MET/ROS1抑制剂，是全球首款ALK激酶抑制剂，也是首个获FDA批准上市的ROS1抑制剂。BMS/再鼎医药的瑞普替尼于2023年11月获FDA批准上市，于2024年5月在国内获批上市。摩熵咨询（原药融咨询）深度报告目前，中国临床肿瘤学会（CSCO）的指南则推荐恩曲替尼和克唑替尼作为IV期ROS1融合阳性NSCLC患者的一线治疗选择，并给予一级推荐。在2024CSCO指南中，ROS1融合阳性的晚期NSCLC的治疗，IV期ROS1融合NSCLC一线治疗部分：新增“Repotrectinib（瑞普替尼）作为Ⅲ级推荐。IV期ROS1融合 NSCLC后线治疗部分，新增“Repotrectinib”作为Ⅲ级推荐。 02 BRAF/NTRK/MET/RET突变NSCLC的临床需求与靶点药物进展除了ROS1基因融合，在肺癌领域，目前已经确定的罕见突变靶点还有BRAF V600E突变、NTRK基因融合、MET 14号外显子跳跃突变、RET融合、KRAS G12C、EGFR 20号外显子插入突变等。（1）非小细胞肺癌罕见突变有较大未满足的临床需求罕见突变靶点药物因基因罕见或研发难度大，目前获批上市的药物不多，BRAF /NTRK/MET /RET 突变NSCLC仍有较大的为满足的临床需求。相信随着研发进展，未来将有更多靶向药问世。摩熵咨询（原药融咨询）深度报告（2）BRAF /NTRK/MET /RET靶点药物仍处于市场导入期由于BRAF V600/NTRK/MET 14 外显子/RET靶点的NSCLC药物近两年刚上市，还处于市场导入阶段。摩熵咨询（原药融咨询）深度报告达拉非尼+曲美替尼首个适应症为黑色素瘤，2019年12月获批上市， NSCLC适应症为2021年4月获批上市。销售额额表现较好，2023年已达7.8亿元。治疗MET外显子14突变药物中，赛沃替尼尽管为二级推荐，但销售额表现较好，2023年达4.11亿元，主要是上市时间较早，其他三款药物均2023年刚获批上市。摩熵咨询（原药融咨询）深度报告（3）BRAF突变NSCLC治疗推荐 NSCLC的BRAF突变率为2%-4%，其中最常见类型为BRAF V600突变。BRAF突变作为肺癌不良预后因子，传统化疗和免疫治疗对BRAF V600突变人群均疗效有限。多个靶向药物获批用于晚期NSCLC的同时，BRAF V600突变NSCLC患者却面临着长期无靶向药可用的困境。随着达拉非尼+曲美替尼的双靶联合治疗方案于2022年3月获得国家药品监督管理局（NMPA）批准用于治疗BRAF V600E突变阳性的转移性NSCLC患者，BRAF V600突变也从既往的“无药可用”进入了“有靶有药”的时代。在国内2024版CSCO指南中，达拉非尼+曲美替尼被列入I级推荐，成为我国BRAF V600突变晚期NSCLC患者的标准治疗方案。（4）NTRK融合NSCLC治疗推荐 NTRK融合基因是近年来非小细胞肺癌（NSCLC）中备受关注的罕见驱动基因变异之一，其突变频率在中国肺癌人群中极低，仅占0.18%。NTRK突变的NSCLC最常见于具有腺癌组织学和最少吸烟的年轻患者。在CSCO新版指南中，恩曲替尼、拉罗替尼作为一线治疗的推荐由原来的Ⅲ级推荐上调为Ⅰ级推荐（3类证据），一线治疗的Ⅱ级推荐继续参考Ⅳ期无驱动基因NSCLC一线治疗的Ⅱ级推荐部分，一线治疗的Ⅲ级推荐则变更为参考Ⅳ期无驱动基因NSCLC一线治疗的Ⅲ级推荐部分。拉罗替尼于2018年被FDA批准用于携带NTRK基因融合的成人和儿童实体肿瘤患者。恩曲替尼于2019年被FDA批准用于12岁以上的存在NTRK融合的实体肿瘤患者的成人和儿童患者。（5）MET 14外显子跳跃突变NSCLC治疗推荐 MET 14外显子跳跃突变在NSCLC中发生率为1%~3%，在肺肉瘤样癌中发生率则高达13%~22%。对于此类患者，新版指南一线治疗中，上调“特泊替尼”为I级推荐，新增“谷美替尼”“伯瑞替尼”作为I级推荐；一线治疗新增“赛沃替尼”为II级推荐。特泊替尼于2021年2月3日获FDA加速批准，2023年12月获得NMPA批准用于治疗MET14 外显子跳跃突变的晚期或转移性NSCLC。谷美替尼、伯瑞替尼分别于2023年3月、11月获NMPA附条件批准用于MET 14外显子跳跃突变的局部晚期或转移性NSCLC的治疗。伯瑞替尼（Vebreltinib）研发现状图片来源：摩熵医药全球药物研发数据库（6）RET 融合突变NSCLC治疗推荐 RET基因融合突变在NSCLC中的发生率为1%~2%，可诱导RET信号通路配体非依赖性激活，与MAPK通路改变互斥，但可与其他突变同时出现。新版指南将“塞普替尼”的I级推荐的证据类型由3类改为1类，同时上调“普拉替尼”为I级推荐，后线推荐则变更为参考Ⅳ期无驱动基因NSCLC一线治疗的II/III级推荐部分。塞普替尼于2022年9月获NMPA附条件批准用于治疗RET基因融合阳性NSCLC患者。普拉替尼于2023年6月获NMPA批准用于RET基因融合阳性NSCLC成人患者的一线治疗。结语非小细胞肺癌的治疗正在经历一场革新，从ROS1融合到BRAF、NTRK、MET、RET等少见靶点，每一种基因突变的发现都为患者带来了新的治疗曙光。尽管这些罕见突变的治疗药物尚处于市场导入期，但其临床价值的显现已不可小觑。未来，随着更多创新药物的研发与上市，以及治疗指南的不断更新与完善，NSCLC患者将拥有更多个性化、精准化的治疗选择，进一步提升生存质量与生存期。非小细胞肺癌药物，下期内容预告目录一、2024年NSCLC治疗前沿：PD-(L)1和VEGF抑制剂的市场表现与临床应用近期将持续更新，敬请期待 END 本文为原创文章，转载请留言获取授权联系我们，体验摩熵医药更多专业服务会议合作园区服务数据库咨询定制服务媒体合作点击阅读原文，了解更多品牌升级详情！

上市批准CSCO会议免疫疗法

2024-10-25

·奇点网

发挥威力，“解绑”是关键。

*仅供医学专业人士阅读参考就在本月初，国家药品监督管理局（NMPA）正式批准德曲妥珠单抗（T-DXd），用于治疗存在HER2突变且既往接受过至少一种系统治疗的不可切除的局部晚期或转移性非小细胞肺癌（NSCLC）成人患者，成为我国首个且唯一批准的HER2突变肺癌靶向治疗药物。T-DXd是一种HER2靶向的抗体药物偶联物（ADC）。这类药物常被誉为“魔法子弹”，通过将强效的细胞毒性药物与靶向抗体结合，选择性地攻击肿瘤细胞，避免对健康组织的广泛损伤。当ADC的抗体结构特异性识别并结合肿瘤细胞表面的特定抗原后，会经内吞作用被肿瘤细胞内化并释放出细胞毒性药物，进而诱导肿瘤细胞死亡，同时部分药物还具有旁观者效应，即释放的药物能够扩散到附近未表达目标抗原的肿瘤细胞，扩大抗肿瘤范围。即使是如此奇妙的魔法子弹，也会有打不穿的堡垒。近日，美国纪念斯隆-凯特琳癌症中心Sarat Chandarlapaty团队发表在Cell Reports Medicine期刊上的最新研究，揭示了HER2靶向ADC药物的耐药机制。他们发现，EGFR表达水平升高时会促使其与HER2形成异二聚体，阻碍HER2靶向ADC药物被细胞内化，导致细胞对药物吸收减少。联合使用EGFR靶向抗体药物可以提高内化速率，从而显著增强HER2靶向ADC药物在EGFR过表达肿瘤中的抗肿瘤效果。论文首页截图德曲妥珠单抗（T-DXd）是HER2靶向ADC的代表性药物。此前的研究结果表明，在一些癌症类型中，即便HER2高表达，T-DXd的疗效并不一致。例如在HER2阳性转移性结直肠癌（CRC）患者中，客观反应率（ORR）仅为27.5%到45.3%，而HER2阳性乳腺癌的ORR高达70.6%。Sarat Chandarlapaty团队注意到，虽然HER2在3%-5%的CRC患者中过表达，但大多数CRC患者同时还表现出EGFR过表达。因此，他们推测可能是EGFR的存在干扰了HER2靶向ADC药物的疗效。在这项研究中，研究者们首先对18例HER2阳性CRC患者样本进行受体酪氨酸激酶蛋白表达谱的分析，结果表明EGFR在这些样本中普遍过表达。他们利用体外实验观察到，在HER2阳性且EGFR过表达的CRC细胞系中，敲低EGFR会加快T-DXd被细胞内化的速度，使内化速率增加1.5倍；相反，在EGFR低表达的CRC细胞系中，EGFR过表达则会抑制T-DXd的内化速率，降低1.3-1.4倍。尽管EGFR表达水平发生了变化，但HER2的总表达量或其膜定位并没有受到影响，这表明EGFR的作用主要是通过抑制T-DXd的内化来削弱疗效，而不是影响HER2的表达。染色后观察T-DXd在CRC细胞中的运输进一步研究揭示，EGFR的作用主要在于能够与HER2形成异二聚体。正常情况下，T-DXd中的抗体与HER2结合后，会促进HER2聚集形成同源二聚体，从而引发内吞作用，将ADC药物转运到溶酶体等酸性细胞器中，释放毒性药物并诱导肿瘤细胞死亡。然而，EGFR过表达的细胞中，HER2/EGFR异源二聚体的数量增加3倍，而HER2/HER2同源二聚体减少2倍，直接减少了HER2靶向AD药物的内化效率，导致抗肿瘤疗效下降。于是，研究者们尝试给魔法子弹再配上一枚穿甲弹。那就是抗EGFR单抗。机制西妥昔单抗和Pembrolizumab是批准用于KRAS野生型CRC的抗EGFR单抗，其作用机制之一是诱导EGFR的内化。研究者们发现，在EGFR扩增表达的CRC细胞系中，与T-DXd单药治疗相比，西妥昔单抗或者Pembrolizumab的联合治疗分别使T-DXd的内化速率提高1.8倍和2.6倍。研究者们还构建了两种患者来源的异种移植模型小鼠。结果显示，在ERBB2（HER2编码基因）扩增18.4倍的CRC小鼠中，联合治疗的肿瘤生长抑制效果相比于西妥昔单抗或T-DXd单药治疗，分别提高73.59%和43.65%；在ERBB2扩增9倍的CRC小鼠中，分别提高98.25%和94.97%。对于KRAS突变型CRC，西妥昔单抗以一己之力表现束手无策，但与T-DXd联手时能够继续发挥其“穿甲弹”的效果，联合治疗相比于T-DXd单药治疗的肿瘤生长抑制效果提高62.4%。联合EGFR靶向的单抗可以促进肿瘤细胞内吞HER2靶向的ADC药物，提高抗肿瘤效果不仅限于结直肠癌，在头颈部鳞状细胞癌、胶质母细胞瘤、食管癌等其它发生EGFR扩增的肿瘤模型中，西妥昔单抗的加入也会提高T-DXd的内化速率，减缓肿瘤生长。对于携带KRAS突变和ERBB2扩增的胰腺癌小鼠，联合治疗的肿瘤生长抑制效果比T-DXd单药提高85%以上。为验证临床价值，研究者们对恩美曲妥珠单抗（T-DM1，另一种HER2靶向ADC）相关的一项篮子试验（NCT02675829）的患者样本进行分析，结果显示EGFR高表达与T-DM1治疗效果较差相关。EGFR表达与T-DM1治疗效果相关，靶向EGFR的联合治疗方法在多种癌症类型中适用总之，这项研究结果表明，EGFR过表达是T-DXd耐药的潜在机制，可通过针对EGFR的联合治疗策略来克服，在多种癌症类型中展现出令人惊叹的治疗潜力。此外，根据患者样本的分析结果，研究者们还提出一种假设，检测EGFR/HER2异二聚化或许可以预测对HER2靶向ADC药物的疗效，这需要进一步设计临床试验来进行评估。参考文献：[1]https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(24)00539-1本文作者丨张艾迪

抗体药物偶联物临床结果