PTEN

作者｜小麦奥希替尼是目前全球临床上使用最广泛的EGFR靶向药，将中位无进展生存期延长至18.9个月，2023年创下57.99亿美元的销售额，然而奥希替尼也面临严峻的耐药问题。为了克服奥希替尼耐药性，一些新策略如EGFR的PROTACs、双抗以及ADC等纷纷涌现，给后奥希替尼时代带来了曙光。   01  EGFR抑制剂耐药性机制EGFR是一种受体酪氨酸激酶（RTK），由28个外显子和27个内含子组成，包括细胞外结构域，跨膜结构域和细胞内结构域三个组成部分。EGFR在人上皮细胞的信号转导途径中起关键作用，它的异常与很多疾病相关，如在非小细胞肺癌（NSCLC）中约35%的患者由EGFR基因突变引起。已经有很多EGFR靶向药获批上市，如1-3代EGFR小分子抑制剂和EGFR/Met双抗等。目前获批上市的EGFR小分子靶向药中奥希替尼是最畅销的药物，2023年全球销售额达到57.99亿美元，然而很多患者在使用奥希替尼之后会出现耐药问题，为了克服奥希替尼耐药问题，很多公司开发新的药物。奥希替尼继发耐药机制包括EGFR靶向和非EGFR脱靶性两种（图1）[1]。1)靶向耐药: 在仍依靠 EGFR通路的情况下，肿瘤细胞发生奥希替尼耐药，如T790M缺失、C797x突变、奥希替尼18号外显子L718Q/V位点突变和G724S突变等。2)非EGFR脱靶性耐药:肿瘤细胞通过其它途径绕过 EGFR通路，持续增殖，如CCNE1扩增、MET扩增、HER2扩增、AKT/PTEN/PIK3CA突变、致癌基因融合（FGFR3、RET、NTRK）等。 图1. EGFR抑制剂耐药机制  02  靶向EGFR的PROTACsPROTAC因其可以降解整个蛋白而不是仅仅抑制蛋白酶活性而备受关注，尤其是针对易突变蛋白，PROTAC有望克服其耐药问题。全球有多家企业布局EGFR PROTACs。● 海思科HSK40118：全球首款，进入临床海思科自主研发的口服EGFR-PROTAC HSK40118的临床试验申请于2023年3月15日获得NMPA批准，用于治疗不可手术的、携带EGFR突变的晚期NSCLC患者，成为全球首款进入临床的EGFR PROTAC药物。●  CFT8919：变构 BiDAC™ 降解剂，进入临床CFT8919是由C4 Therapeutics研发的具有口服生物利用度的变构 BiDAC™ 降解剂，对携带EGFR L858R 突变具有良好的活性和选择性，同时，CFT8919对像T790M或C797S突变的EGFR继发耐药突变有效。2023年5月30日，贝达与C4 Therapeutics达成合作协议，贝达向C4支付3500万美元，包括1000万美元的首付款和贝达投资(香港)有限公司将一次性认购C4T 2500万美元股权，取得在中国（包括香港、澳门和台湾地区）开发、制造和商业化CFT8919的权利，并可获得前述区域以外约定比例的销售提成[2]。2023年12月5日，CFT8919的临床试验申请已获得NMPA批准开展，拟用于携带EGFR突变的局晚期或晚期NSCLC患者。除此之外，临床前也有很多在研的EGFR PROTACs，如百济的EGFR CDAC，它对多种EGFR突变都有抑制活性，在奥希替尼敏感或耐药肿瘤中都有很好的抑瘤活性（图2）。 图2. 百济的EGFR CDAC活性  02  靶向EGFR的双特异性抗体除了C797S突变，还有其它因素导致奥希替尼耐药，如MET扩增等，因此EGFR/Met双抗有望解决奥希替尼耐药问题。● 强生埃万妥单抗:EGFR/c-Met，一线疗法获批埃万妥单抗是强生研发的首款获批上市的靶向EGFR ex20ins（EGFR 20号外显子突变）突变的EGFR/c-Met双抗药物，EGFR ex20ins是EGFR第三大突变类型，于2021年5月获FDA加速批准用于二线治疗EGFR ex20ins患者。强生对埃万妥单抗寄予厚望，一方面探索埃万妥单抗单药或联合治疗EGFR 突变NSCLC患者一线疗法，另一方面探索埃万妥单抗对奥希替尼耐药患者的疗效。2023年8月，强生向FDA递交了埃万妥单抗的补充生物制品许可申请(sBLA)，与化疗联用一线治疗携带EGFR外显子20插入突变的局部晚期或转移性NSCLC患者。2024年3月1日，强生宣布FDA已批准埃万妥单抗联合化疗一线治疗EGFR外显子20插入突变的局部晚期或转移性NSCLC患者。结合奥希替尼耐药机制，埃万妥单抗联合三代EGFR抑制剂拉泽替尼方案获得广泛关注。2023年9月，埃万妥单抗联合拉泽替尼和化疗治疗奥希替尼耐药的一项3期MARIPOSA-2试验取得积极结果：与化疗相比，埃万妥单抗加化疗以及埃万妥单抗加拉泽替尼加化疗的无进展生存期（PFS）显著延长，疾病进展或死亡的风险比（HR）分别为0.48和0.44，中位PFS分别为6.3个月和8.3个月，化疗组为4.2个月（图3）[3]。通过研究者评估得到一致的 PFS 结果，埃万妥单抗加化疗以及埃万妥单抗加拉泽替尼加化疗的疾病进展或死亡的HR分别为0.41和0.38，中位PFS分别为8.2个月和8.3个月，化疗组为4.2个月。 图3. MARIPOSA-2试验结果2023年10月26日，埃万妥单抗在国内的上市申请获药监局受理。● 百利天恒SI-B001：EGFR/HER3，Ⅲ期临床除了埃万妥单抗之外，临床上还有很多在研的靶向EGFR的双抗药物，如百利天恒的Izalontamab（SI-B001）等。SI-B001是由百利天恒基于自主建立的SEBA平台独立研发的靶向 EGFR/HER3 的双抗药物，已在多个 II 期临床试验中表现了具备突破性疗效的有效性和良好的耐受性。HER3属于受体酪氨酸激酶EGFR家族。据估计，在EGFR TKI治疗后，约 83% 的原发性NSCLC和 90% 的晚期EGFR突变肿瘤会表达HER3。靶向EGFR/HER3 的双抗有望解决解决奥希替尼耐药问题。2023年6月，百利天恒在药物临床试验登记与信息公示平台登记了SI-B001的第一项3期临床试验，旨在评估SI-B001联合多西他赛对比多西他赛二线治疗局部晚期或转移性无驱动基因变异的非小细胞肺腺癌和肺鳞癌患者的有效性和安全性。SI-B001在结肠癌SW48异种移植、头颈部鳞状细胞癌FaDu异种移植和食管癌KYSE-150异种移植中显示明显的抗肿瘤功效（图4）[4]。 图4. SI-B001的抗肿瘤功效SI-B001在EGFR/ALK野生型非小细胞肺癌的肺鳞癌后线（中位四线）的初步临床试验显示积极的疗效：疾病控制率（DCR）为 87.50%（7/8），其中部分缓解（PR）为12.50%（1/8）；非小细胞肺癌二线化疗药物多西他赛的历史数据，DCR为48.54%（50/103），其中PR为5.82%（6/103）[5]。  03  第一三共：HER3-Dxd已申报上市在NSCLC中，HER3表达与晚期疾病、转移时间缩短和生存率降低有关。HER3的高表达也与EGFR TKIs耐药有关，所以人们寄希望于HER3靶向药能解决奥希替尼耐药问题。目前尚无靶向HER3疗法被获批上市，HER3-DXd（Patritumab deruxtecan）是由第一三共原研的一款靶向HER3的ADC药物，是目前研发进展最快的HER3 ADC药物，通过半胱氨酸定点偶联连接方式将马来酰亚胺-GGFG接头连接HER3单抗patritumab和拓扑异构酶I抑制剂deruxtecan而得。HER3-DXd（Patritumab deruxtecan）于 2021 年 12 月获FDA授予突破性疗法认定（BTD），用于治疗在第三代EGFR TKI和含铂化疗期间或之后疾病进展的EGFR突变局部晚期或转移性NSCLC患者。此前，Patritumab Deruxtecan在一项旨在评估其在使用EGFR TKI治疗和含铂化疗疾病进展后的EGFR突变局部晚期或转移性NSCLC患者中安全性和有效性的全球、多中心、开放标签、双臂2期HETHENA-Lung01（NCT04619004）试验取得积极结果。研究结果显示：截至 2023 年 5 月 18 日，中位研究持续时间为 18.9 个月（范围为 14.9-27.5 个月）。BICR确认的ORR为29.8%（95%CI，23.9至36.2）;中位缓解持续时间为 6.4个月；中位无进展生存期为5.5个月；中位总生存期为 11.9 个月。既往接受过奥希替尼和铂类化疗（PBC）患者亚组具有相似的结果（图5）[6]。 图5. HETHENA-Lung01试验抗肿瘤活性对30 名来自疗效人群的脑部转移患者颅内反应分析（通过 CNS BICR），这些患者既往未接受过脑部放疗。在这些患者中，有7例发现了目标病灶；其余只有非靶病灶。CNS ORR（根据 CNS BICR）为 33.3%，有9个中枢神经系统 CR（其中8 例为仅具有非目标病灶的患者）和1例PR。这些反应基于单独的CT成像（5个 CR和1个PR）、单独的 MRI（2个CR）或CT成像和MRI确认（2个CR）。疾病稳定（包括非CR/非进展性疾病）的最佳CNS反应[PD]）PD的发生率为43.3%（13/30）和13.3%（4/30）（图6）。 图6 . Patritumab Deruxtecan对脑转移NSCLC患者疗效Patritumab Deruxtecan在已知和未知的EGFR TKI耐药机制谱中都产生了抗肿瘤活性（图7）[7]。57例中有23例（不包括T790M）已知EGFR相关耐药机制患者，这些患者确诊的ORR为35%（CR/PR，8；SD，7；PD，5；NE，3）。57 例中有13例具有EGFR非依赖性耐药机制的患者，确认的ORR为46%（CR/PR，6；SD，4；PD，2；NE，1）。57例中有21例具有其他/未知耐药机制的患者，确诊的 ORR为 38%（CR/PR，8 例；SD，8；PD，2；NE，3）。 图7. Patritumab Deruxtecan对EGFR TKI耐药患者疗效2023年10月20日，默沙东与第一三共就包括Patritumab deruxtecan在内的三款ADC药物达成了高达220亿美元的合作协议。基于2期HERTHENA-Lung01积极结果，2023年12月22日，第一三共和默沙东共同宣布patritumab deruxtecan的BLA获FDA受理并予以优先审评，用于治疗既往至少接受过两种系统治疗的EGFRm局部晚期或转移性NSCLC， PDUFA日期为2024年6月26日, patritumab deruxtecan成为首款申报上市的HER3 ADC。  写在最后  EGFR是一个易突变的蛋白，奥希替尼是目前全球最畅销的EGFR抑制剂，但长期使用容易产生耐药问题，后奥希替尼时代已悄然来临。针对奥希替尼耐药问题，各大药企各显神通，第四代EGFR抑制剂、EGFR的PROTACs、双抗、ADC等纷纷上桌，多项试验传来了好消息，相信不久的将来奥希替尼耐药问题必将被克服。参考文献1.Yufeng Li et.al, Toward the next generation EGFR inhibitors: an overview of osimertinib resistance mediated by EGFR mutations in non‑small cell lung cancer, Cell Communication and Signaling (2023) 21:712.强强联手｜贝达药业与美国C4 Therapeutics达成合作引进CFT8919项目3.Amivantamab plus chemotherapy with and without lazertinib in EGFRmutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study4.Anti-tumor efficacy of SI-B001, a novel EGFR×HER3 bispecific antibody, against EGFR-driven epithelial tumors alone or in combination with paclitaxel and carboplatin5.医药魔方：全球首款！百利天恒HER3/EGFR双抗启动III期临床6.Helena A. Yu, MD et.al, HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor–Mutated Non–Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy, J Clin Oncol 41:5363-53757.Pasi A. Jänne et.al, Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor– Resistant, EGFR-Mutated Non–Small Cell Lung Cancer, Cancer Discov 2022;12:74–89共建Biomedical创新生态圈！如何加入BiG会员？

Leading Contract Research Organization to carry out pharmacological studies, part of planned FDA Investigational New Drug (IND) applicationTORONTO and HAIFA, Israel, March 22, 2024 (GLOBE NEWSWIRE) -- NurExone Biologic Inc. (TSXV: NRX) (Germany: J90) (the “Company” or “NurExone”), a pioneering biopharmaceutical company, developing regenerative medicine therapies, is proud to announce a strategic service agreement with Vivox Ltd. (“Vivox”), a leading provider of animal testing and services in Israel to biotech and pharmaceutical companies. This large-scale animal testing represents a significant step towards filing an Investigational New Drug (IND) application in the US for NurExone’s ExoPTEN therapy for spinal cord injury (SCI). Under the terms of the agreement, Vivox will provide Contract Research Organization (CRO) services to NurExone, as a prerequisite to commencing Human Trials under the planned IND. The scope of the services to be provided includes the carrying out of experiments by Vivox on a total of 100 rats, divided into 5 different experiments. Every experiment involves comprehensive care and monitoring of the rats. In the experiments, some of the test subjects will receive the ExoPTEN active ingredient and a second group will receive a placebo and/or naïve exosomes (without the PTEN active ingredient). The typical treatment period is approximately 2 months. The aim of this series of tests is to evaluate the optimal dosage of ExoPTEN in various pharmacologically relevant rodent models of spinal cord. The agreement underscores both companies' commitment to accelerating innovative therapies for SCI. "We are pleased to commission Vivox to conduct a series of closely monitored experiments on a large group of laboratory animals as part of the ExoPTEN IND enabling studies. The testing will encompass mobility, behavior, motor and sensory recovery of rats following Spinal Cord Injury and treatment with ExoPTEN," said Dr. Lior Shaltiel, CEO of NurExone. "We anticipate that this independent and detailed analysis will corroborate and expand upon the encouraging results observed in numerous laboratory experiments." NurExone believes that the ExoPTEN therapy holds significant promise as a potential treatment for SCI. Preclinical studies have demonstrated its ability to promote neural regeneration and functional recovery in animal models. By collaborating with Vivox, NurExone aims to accelerate the development and regulatory path of ExoPTEN, to bring this potentially transformative treatment to patients in need. About Vivox Ltd. Vivox is a leading CRO in Israel, specializing in in-vivo and in-vitro preclinical services for pharmaceutical, biotech, and medical device companies. Established in 2018, Vivox has conducted numerous successful experiments and operates a state-of-the-art facility in Yokne’am-Illit. With a focus on accuracy and efficiency, Vivox offers a range of services including toxicology expertise, disease models, surgical services, and analytics. The company is dedicated to helping pharmaceutical firms develop innovative medicines through tailored studies conducted under strict safety measures for high-quality results. About NurExone Biologic Inc. NurExone Biologic Inc. is a TSXV listed pharmaceutical company that is developing a platform for biologically-guided exosome-based therapies to be delivered, non-invasively, to patients who have suffered Central Nervous System injuries. The Company’s first product, ExoPTEN for acute spinal cord injury, was proven to recover motor function in 75% of laboratory rats when administered intranasally. ExoPTEN has been granted Orphan Drug Designation by the FDA. The NurExone platform technology is expected to offer novel solutions to drug companies interested in noninvasive targeted drug delivery for other indications. For additional information, please visit www.nurexone.com or follow NurExone on LinkedIn, Twitter, Facebook, or YouTube. For more information, please contact: Dr. Lior ShaltielChief Executive Officer and DirectorPhone: +972-52-4803034Email: info@nurexone.com Thesis Capital Inc.Investment Relation - CanadaPhone: +1 905-347-5569Email: IR@nurexone.com Dr. Eva ReuterInvestment Relation - GermanyPhone: +49-69-1532-5857Email: e.reuter@dr-reuter.eu Cautionary Statement Regarding Forward-Looking Statements This press release contains certain "forward-looking information" within the meaning of applicable Canadian securities legislation. Such forward-looking information and forward-looking statements are not representative of historical facts or information or current condition, but instead represent only the Company's beliefs regarding future events, plans or objectives, many of which, by their nature, are inherently uncertain and outside of the Company's control. Often, but not always, forward-looking statements and information can be identified by the use of words such as "plans", "expects" or "does not expect", "is expected", "estimates", "intends", "anticipates" or "does not anticipate", or "believes", or variations of such words and phrases or state that certain actions, events or results "may", "could", "would", "might" or "will" be taken, occur or be achieved. Forward-looking statements in this news release include statements relating to: the benefits, terms, and scope of the strategic agreement, including the stated nature, goals, and manner of which experiments will be conducted; the ongoing commitment of the Company to further therapies for SCI; the anticipation that an independent and detailed analysis will corroborate and expand upon the encouraging results observed in numerous laboratory experiments; ExoPTEN therapy holding significant promise as a potential treatment for SCI; the Company’s stated goals for accelerating the development and regulatory path of ExoPTEN; and the expectation of the NurExone platform technology will offer novel solutions to drug companies interested in noninvasive targeted drug delivery for other indications. Forward-looking information in this press release are based on certain assumptions and expected future events, namely: the Company’s ability to realize upon the benefits, terms, and scope of the strategic agreement; the Company’s ability to keep its ongoing commitment of the Company to further therapies for SCI; that an independent and detailed analysis will corroborate and expand upon the encouraging results observed in numerous laboratory experiments; the ExoPTEN therapy has the ability to be a significant promise as a potential treatment for SCI; the Company’s ability to realize upon the stated goals for accelerating the development and regulatory path of ExoPTEN; and the Company’s ability to realize upon its expectation of the NurExone platform technology to offer novel solutions to drug companies interested in noninvasive targeted drug delivery for other indications. These statements involve known and unknown risks, uncertainties and other factors, which may cause actual results, performance or achievements to differ materially from those expressed or implied by such statements, including but not limited to: the Company’s inability to realize upon the benefits, terms, and scope of the strategic agreement; the Company’s inability to keep its ongoing commitment of the Company to further therapies for SCI; that an independent and detailed analysis will not corroborate and expand upon the encouraging results observed in numerous laboratory experiments; the ExoPTEN therapy will not be a significant promise as a potential treatment for SCI; the Company’s inability to realize upon the stated goals for accelerating the development and regulatory path of ExoPTEN; and the Company’s inability to realize upon its expectation of the NurExone platform technology to offer novel solutions to drug companies interested in noninvasive targeted drug delivery for other indications. Readers are cautioned that the foregoing list is not exhaustive. Readers are further cautioned not to place undue reliance on forward looking statements, as there can be no assurance that the plans, intentions or expectations upon which they are placed will occur. Such information, although considered reasonable by management at the time of preparation, may prove to be incorrect and actual results may differ materially from those anticipated. Although the Company believes that the assumptions and factors used in preparing, and the expectations contained in, the forward-looking information and statements are reasonable, undue reliance should not be placed on such information and statements, and no assurance or guarantee can be given that such forward-looking information and statements will prove to be accurate, as actual results and future events could differ materially from those anticipated in such information and statements. The forward-looking information and forward-looking statements contained in this press release are made as of the date of this press release, and the Company does not undertake to update any forward-looking information and/or forward-looking statements that are contained or referenced herein, except in accordance with applicable securities laws. Neither TSX-V nor its Regulation Services Provider (as that term is defined in the policies of the TSX-V) accepts responsibility for the adequacy or accuracy of this release.

引言胶质母细胞瘤是最致命的原发性脑肿瘤，携带着能够启动和维持恶性表型并增强治疗抵抗力的胶质母细胞（GSCs）。尽管PTEN在胶质母细胞瘤中经常发生突变，但PTEN在PTEN完整的GSCs中的功能和调控尚不清楚。2024年3月20日，南京医科大学钱旭，尤永平和汪秀星共同通讯在Science Translational Medicine在线发表题为“Reactivating PTEN to impair glioma stem cells by inhibiting cytosolic iron-sulfur assembly”的研究论文，该研究发现PTEN直接与MMS19相互作用，并竞争性地破坏分化的胶质瘤细胞中基于MMS19的细胞质铁硫（Fe-S）簇装配（CIA）机制。与匹配的分化的胶质瘤细胞相比，PTEN在GSCs中的胱氨酸（C）211位点特异性地发生琥珀酸化。同位素示踪结合质谱分析证实，由于在GSCs中高度活化的新生嘌呤合成途径中由腺苷琥珀酸合酶（ADSL）产生的富马酸促进了PTEN C211的琥珀酸化。这种修饰取消了PTEN与MMS19之间的相互作用，重新激活了GSCs中的CIA机制途径。在功能上，通过重新表达PTEN C211S突变体，通过shRNA去除ADSL，或通过美国食品药品监督管理局批准的处方药乙酰半胱氨酸（NAC）消耗富马酸，抑制了GSC的维持。通过重新表达PTEN C211S或使用NAC治疗使GSC源性脑肿瘤对于替莫唑胺和放射疗法，即胶质母细胞瘤患者的标准治疗，产生了敏感性，通过减缓CIA机械介导的DNA损伤修复。这些发现揭示了一种立即可行的策略，通过重组NAC的联合治疗来靶向GSCs治疗胶质母细胞瘤。胶质母细胞瘤（GBM）是最常见和最恶性的原发性脑肿瘤。目前的治疗方案是最大限度地切除手术，随后进行同时化疗和放疗以及辅助化疗，但只能提供缓解治疗，从诊断时间算起，患者的中位总生存期不到15个月。GBM含有由胶质母细胞（GSCs）强化的多种细胞群的细胞层级结构，这些细胞群在功能上通过广泛的自我更新和多线分化来定义。GSCs在体内形成的肿瘤与患者肿瘤相似，使它们成为脑肿瘤研究的良好模型。GSCs对传统化疗和放疗的抵抗与非干细胞或分化的胶质细胞（DGCs）相比也支持了它们在临床上的重要性。利用GSCs的调节可能为改善GBM患者的临床结果提供关键信息。PTEN是一个众所周知的肿瘤抑制基因，它转移到细胞膜上，在那里通过去磷酸化和抑制磷脂酰肌醇3-激酶（PI3K）信号来抑制磷脂酰肌醇（3,4,5）-三磷酸（PIP3）依赖性过程，如AKT的膜招募和活化。我们最近报告了PTEN的琥珀酸化，这是PTEN的最近鉴定的翻译后修饰之一，阻碍了它在细胞膜上的定位，从而减弱了它对PI3K/AKT途径的抑制作用。除了通过其脂质磷酸酶活性对PI3K/AKT的抑制作用外，我们报道了PTEN作为蛋白质磷酸酶的功能，它去磷酸化磷酸化的磷酸甘油酸激酶1（PGK1），抑制了PGK1的糖酵解酶活性，从而抑制了糖酵解和脑肿瘤的生长。除了其脂质和蛋白质磷酸酶活性外，PTEN作为一个复合调节因子，展示了复杂的机制，包括调节染色质稳定性、DNA损伤修复和基因转录。尽管在GBMs中经常发生突变，但在大量GSCs中发现PTEN是完整的。然而，PTEN在GSCs中的调节和临床意义尚未明确定义。优先吸收铁是GSCs的特点之一。铁硫（Fe-S）簇是许多参与基本生物过程的蛋白质的无机辅因子。生成这些簇需要线粒体Fe-S组装机和细胞质铁硫（Fe-S）簇组装（CIA）机的成员之间的协调活动。后一条途径充当一个通道，其中Fe-S含量的辅因子从线粒体Fe-S组装中生成，并通过一系列蛋白质最终被结合到调控细胞周期或DNA复制和修复的细胞质或核蛋白中。这个过程的一个关键终端适配器是MMS19同源物，它与许多重要的DNA代谢和DNA损伤修复相关的蛋白质结合。已经鉴定了CIA机械途径中的核心组装蛋白和特定的Fe-S靶向蛋白。然而，CIA机械途径的调节仍然是一个巨大的空白。PTEN在C211位点的琥珀化对GSC的维持至关重要（Credit: Science Translational Medicine）该研究证明PTEN直接与MMS19相互作用，并竞争性地干扰了依赖于MMS19的CIA机械。在GSCs中高度活跃的嘌呤合成途径为PTEN在C211位点（PTEN C211sc）的琥珀酸化提供了丙二酸，这消除了PTEN与MMS19之间的相互作用，从而减轻了PTEN对CIA机械的抑制作用，促进了GSC的维持和脑肿瘤发生。原文链接https://www.science.org/doi/10.1126/scitranslmed.adg5553责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述