更新于：2024-05-01

SOAT1

酰基辅酶A：胆固醇酰基转移酶-1

更新于：2024-05-01

基本信息

别名

ACACT、ACACT1、ACAT

+ [10]

简介

Catalyzes the formation of fatty acid-cholesterol esters, which are less soluble in membranes than cholesterol (PubMed:16154994, PubMed:16647063, PubMed:9020103, PubMed:32433614, PubMed:32433613, PubMed:32944968). Plays a role in lipoprotein assembly and dietary cholesterol absorption (PubMed:16154994, PubMed:9020103). Utilizes oleoyl-CoA ((9Z)-octadecenoyl-CoA) preferentially as susbstrate: shows a higher activity towards an acyl-CoA substrate with a double bond at the delta-9 position (9Z) than towards saturated acyl-CoA or an unsaturated acyl-CoA with a double bond at the delta-7 (7Z) or delta-11 (11Z) positions (PubMed:11294643, PubMed:32433614).

关联

项与 SOAT1 相关的药物

helvamide

靶点-

作用机制

SOAT1抑制剂 [+1]

在研机构

Kitasato University

原研机构

Kitasato University

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

clonoamide

靶点-

作用机制

SOAT1抑制剂 [+1]

在研机构

Kitasato University [+1]

原研机构

Chugai Pharmaceutical Co., Ltd. [+1]

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

DuP-128 analogs

靶点

SOAT1

作用机制

SOAT1抑制剂

在研机构-

原研机构

DuPont Pharma, Inc.

在研适应症-

非在研适应症

动脉粥样硬化 [+1]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

项与 SOAT1 相关的临床试验

NCT03669549 / Terminated临床2期

A Multicenter Dose-Titration Open-Label Study of Nevanimibe Hydrochloride for the Treatment of Classic Congenital Adrenal Hyperplasia

This is a multicenter, intra-subject dose-titration open-label study of nevanimibe hydrochloride (HCl) for the treatment of classic congenital adrenal hyperplasia (CAH). Following a Screening Period of approximately 2-14 weeks, eligible subjects will enter a Baseline Period of approximately 2-8 weeks and then a 16-week Treatment Period. It is anticipated that the overall duration of the study per subject will range from 24-42 weeks.

开始日期2018-07-11

申办/合作机构

Millendo Therapeutics US, Inc.

NCT03053271 / Terminated临床2期

A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ATR-101 for the Treatment of Cushing's Syndrome

This is a Phase 2 multicenter, randomized, double-blind, placebo controlled study of ATR-101 to evaluate the efficacy and safety of orally-administered ATR-101 in adults with endogenous Cushing's syndrome. Following wash-out (if needed), all eligible subjects will enter an open-label intra-subject dose-escalation period of 8 weeks' duration, followed either by a double-blind randomized withdrawal period of 4 weeks' duration (if the subject meets randomization criteria) or by an additional open label dosing period of 4 weeks' duration (if the subject does not meet randomization criteria).It is anticipated that the overall duration of the study per subject will range from approximately 16-22 weeks.

开始日期2017-04-13

申办/合作机构

Millendo Therapeutics US, Inc.

NCT02804178 / Completed临床2期

A Phase 2, Multicenter Study of ATR-101 for the Treatment of Congenital Adrenal Hyperplasia

This is a Phase 2 multicenter, single-blind, multiple dose study to evaluate the safety and efficacy of orally administered ATR-101 in subjects with classic congenital adrenal hyperplasia (CAH). Treatment duration will range from a minimum of approximately 2 months to 6 months per subject. A subject may receive a minimum of one dose level or up to a maximum of 5 dose levels, in sequentially increasing dose strengths. Each dose level will last 28 days.

开始日期2016-05-18

申办/合作机构

Millendo Therapeutics, Inc.

100 项与 SOAT1 相关的临床结果

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100 项与 SOAT1 相关的转化医学

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0 项与 SOAT1 相关的专利（医药）

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1,248

项与 SOAT1 相关的文献（医药）

2024-01-25·Scientific reports

Identification of gene signatures and molecular mechanisms underlying the mutual exclusion between psoriasis and leprosy.

Article

作者: You-Wang Lu ; Rong-Jing Dong ; Lu-Hui Yang ; Jiang Liu ; Ting Yang ; Yong-Hong Xiao ; Yong-Jun Chen ; Rui-Rui Wang ; Yu-Ye Li

Leprosy and psoriasis rarely coexist, the specific molecular mechanisms underlying their mutual exclusion have not been extensively investigated. This study aimed to reveal the underlying mechanism responsible for the mutual exclusion between psoriasis and leprosy. We obtained leprosy and psoriasis data from ArrayExpress and GEO database. Differential expression analysis was conducted separately on the leprosy and psoriasis using DEseq2. Differentially expressed genes (DEGs) with opposite expression patterns in psoriasis and leprosy were identified, which could potentially involve in their mutual exclusion. Enrichment analysis was performed on these candidate mutually exclusive genes, and a protein-protein interaction (PPI) network was constructed to identify hub genes. The expression of these hub genes was further validated in an external dataset to obtain the critical mutually exclusive genes. Additionally, immune cell infiltration in psoriasis and leprosy was analyzed using single-sample gene set enrichment analysis (ssGSEA), and the correlation between critical mutually exclusive genes and immune cells was also examined. Finally, the expression pattern of critical mutually exclusive genes was evaluated in a single-cell transcriptome dataset. We identified 1098 DEGs in the leprosy dataset and 3839 DEGs in the psoriasis dataset. 48 candidate mutually exclusive genes were identified by taking the intersection. Enrichment analysis revealed that these genes were involved in cholesterol metabolism pathways. Through PPI network analysis, we identified APOE, CYP27A1, FADS1, and SOAT1 as hub genes. APOE, CYP27A1, and SOAT1 were subsequently validated as critical mutually exclusive genes on both internal and external datasets. Analysis of immune cell infiltration indicated higher abundance of 16 immune cell types in psoriasis and leprosy compared to normal controls. The abundance of 6 immune cell types in psoriasis and leprosy positively correlated with the expression levels of APOE and CYP27A1. Single-cell data analysis demonstrated that critical mutually exclusive genes were predominantly expressed in Schwann cells and fibroblasts. This study identified APOE, CYP27A1, and SOAT1 as critical mutually exclusive genes. Cholesterol metabolism pathway illustrated the possible mechanism of the inverse association of psoriasis and leprosy. The findings of this study provide a basis for identifying mechanisms and therapeutic targets for psoriasis.

2024-01-25·Cancers

Targeting NPC1 in Renal Cell Carcinoma.

Article

作者: Rushaniya Fazliyeva ; Peter Makhov ; Robert G Uzzo ; Vladimir M Kolenko

Rapidly proliferating cancer cells have a greater requirement for cholesterol than normal cells. Tumor cells are largely dependent on exogenous lipids given that their growth requirements are not fully met by endogenous pathways. Our current study shows that ccRCC cells have redundant mechanisms of cholesterol acquisition. We demonstrate that all major lipoproteins (i.e., LDL, HDL, and VLDL) have a comparable ability to support the growth of ccRCC cells and are equally effective in counteracting the antitumor activities of TKIs. The intracellular trafficking of exogenous lipoprotein-derived cholesterol appears to be distinct from the movement of endogenously synthesized cholesterol. De novo synthetized cholesterol is transported from the endoplasmic reticulum directly to the plasma membrane and to the acyl-CoA: cholesterol acyltransferase, whereas lipoprotein-derived cholesterol is distributed through the NPC1-dependent endosomal trafficking system. Expression of NPC1 is increased in ccRCC at mRNA and protein levels, and high expression of NPC1 is associated with poor prognosis. Our current findings show that ccRCC cells are particularly sensitive to the inhibition of endolysosomal cholesterol export and underline the therapeutic potential of targeting NPC1 in ccRCC.

2024-01-04·Journal of agricultural and food chemistry

Biosynthesis of 10-Hydroxy-2-decenoic Acid through a One-Step Whole-Cell Catalysis.

Article

作者: Ke Fang ; Ziting Xu ; Lu Yang ; Quan Cui ; Bowen Du ; Huijing Liu ; Ruiming Wang ; Piwu Li ; Jing Su ; Junqing Wang

10-Hydroxy-2-decenoic acid (10-HDA) is an important component of royal jelly, known for its antimicrobial, anti-inflammatory, blood pressure-lowering, and antiradiation effects. Currently, 10-HDA biosynthesis is limited by the substrate selectivity of acyl-coenzyme A dehydrogenase, which restricts the technique to a two-step process. This study aimed to develop an efficient and simplified method for synthesizing 10-HDA. In this study, ACOX from Candida tropicalis 1798, which catalyzes 10-hydroxydecanoyl coenzyme A desaturation for 10-HDA synthesis, was isolated and heterologously coexpressed with FadE, Macs, YdiI, and CYP in Escherichia coli/SK after knocking out FadB, FadJ, and FadR genes. The engineered E. coli/AKS strain achieved a 49.8% conversion of decanoic acid to 10-HDA. CYP expression was improved through ultraviolet mutagenesis and high-throughput screening, increased substrate conversion to 75.6%, and the synthesis of 10-HDA was increased to 0.628 g/L in 10 h. This is the highest conversion rate and product concentration achieved in the shortest time to date. This study provides a simple and efficient method for 10-HDA biosynthesis and offers an effective method for developing strains with high product yields.

109

项与 SOAT1 相关的新闻（医药）

2022-12-21

·药时代

站在风口上的TYK2抑制剂，国内进展如何？

点击欣赏推介会全程——优秀BD是怎样炼成的？请点击左下方【阅读原文】报名！12月13日，武田制药（Takeda）宣布将从Nimbus Therapeutic购买一款处于临床晚期的口服、选择性变构酪氨酸激酶2（TYK2）抑制剂NDI-034858。根据协议条款，武田将向Nimbus公司支付40亿美元的预付款，并在年度净销售额达到40亿美元和50亿美元后，分别支付两笔10亿美元的里程碑付款，这意味着协议总金额将达到60亿美元。来源：Takeda.comNDI-034858作为Nimbus Therapeutic研发的一款TYK2抑制剂，目前正在评估其用于多种自身免疫性疾病的治疗潜力。在临床前研究中，NDI-034858已展现出卓越的功能选择性和广泛的治疗范围。在I期研究中，NDI-034858显示出良好的耐受性等。12月2日，Nimbus公司公布了NDI-034858 在中至重度斑块状银屑病中的最新IIb期数据，结果表明，在对259例患者的研究中，治疗12周后，与安慰剂相比，研究中达到PASI-75（通过银屑病面积和严重程度指数测量，皮肤病变改善75%）主要终点的患者比例显著更高。除银屑病外，NDI-034858还正在活动性银屑病关节炎中进行一项2b期试验。而且研究人员正在评估用于治疗多种自身免疫性疾病。高达60亿美元的交易价格，一时间让本就处于风口的TYK2抑制剂再次“登上热搜”。那么作为热门靶点，国内TYK2抑制剂研发进展如何？1TYK2——更安全的JAK靶点TYK2，即酪氨酸激酶2蛋白，属于JAK家族的一员。JAK是Janus Kinase的缩写，而Janus取自罗马神话中的“两面神”雅努斯。传说中它有前后两张面孔，所以当年发现它的科学家们借用这个神话人物来形容JAK的标志性特征。JAK家族包括TYK2和JAK1，JAK2，JAK3，其中TYK2是最早被发现的一个。也正是因为发现得早，当时还没有JAK家族的概念，所以并没有按照JAK来命名，这也使得TYK2成为了整个家族里一个特殊的存在。JAK通过细胞因子与JAK相关的I型和II型受体结合进而被激活。激活的JAKs启动转磷酸化，启动信号转导和转录激活因子（STAT）蛋白的招募。通过结合和磷酸化STAT，它被易位到细胞核来修改基因转录。 JAK-STAT信号通路（来源：参考2）JAK-STAT信号通路与多种炎性皮肤疾病的发生相关。同时，JAK激酶也参与一些关键功能，如造血和免疫反应。简单来说，JAK家族各成员靶点相应的适应症如下：JAK1：主要与急性淋巴细胞白血病、急性骨髓性白血病、实体器官恶性肿瘤相关；JAK2：主要与真性红细胞增多症、骨髓纤维化、原发性血小板增多症等疾病相关；JAK3：主要与急性巨幼细胞白血病、T细胞白血病和淋巴瘤等疾病相关；TYK2：主要与皮肤淋巴增殖性疾病、T细胞白血病相关。由于JAK介导的JAK-STAT信号通路会调控多个细胞因子和炎症通路，因此JAK抑制剂一直以来都是研发热点。目前已上市多种JAK抑制剂，其中第一代JAK抑制剂包括芦可替尼（ruxolitinib）、托法替尼（tofacitinib）、巴瑞替尼（baricitinib）、培非替尼（peficitinib）、迪高替尼（delgocitinib）；第二代JAK抑制剂包括乌帕替尼（upadacitinib）、菲卓替尼（fedratinib）、阿布昔替尼（abrocitinib）。不过，以上获批上市的JAK抑制剂大部分选择性不高，存在安全隐患。这是因为，以上JAK抑制剂均与JAK蛋白中的JH1结构域的ATP位点结合，而不同JAK家族成员的JH1结构域又高度相似。这样当细胞内药物浓度增高时，一个JAK抑制剂可能也会影响ATP与其他JAK激酶的结合。也就是说，一款JAK药物对其他JAK家族成员也会造成抑制，进而导致副反应的发生。如2021年9月，FDA给所有JAK关节炎药物作出严重的黑框警告。与此同时，TYK2抑制剂的机会来了。今年9月，FDA批准BMS的Sotyktu（Deucravacitinib）上市，用于治疗中至重度银屑病。Sotyktu通过差异化结构设计，与TYK2的假激酶结构域JH2结合，使TYK2呈非活性构象。其中，不同JAK家族成员的JH2结构并不相同，所以通过抑制JH2，可以只阻断TYK2所支配的IL-23, IL-12和I型干扰素的信号传导，并不会抑制其他的JAK通路。Sotyktu的成功上市，并且不带JAK常见的黑框警告，彻底让TYK2抑制剂站上“风口”。高选择性的TYK2抑制剂可减少泛抑制带来的脱靶效应，TYK2也被认为是潜在的更安全的靶点。据Evaluate Pharma预测，到2026年, Sotyktu销售额将会达到22.62亿美元。2TYK2抑制剂角逐战开启，国内药企谁在布局？目前，国内包括诺诚健华、高光制药、百济神州、海思科等药企，都在开展TYK2靶点药物的研发，且已进入临床研究阶段。根据公开资料整理诺诚健华目前有两款TYK2抑制剂已进入临床试验阶段：一款为ICP-332，该药不仅对TYK2具有强效抑制活性，而且对JAK2的选择性高达约400倍，可减轻因JAK2抑制所致贫血不良反应，目前已启动针对特应性皮炎和银屑病的II期临床；另一款为ICP-488，它可高度特异性结合TYK2 JH2结构域，目前正在I期临床研究阶段。高光制药的TLL-018是一款JAK1/TYK2抑制剂，对JAK1和TYK2具有高度选择性和活性，目前正在全球范围内开展I期临床试验。在中国，该药已获批开展针对银屑病、荨麻疹、类风湿关节炎的临床研究。其中，针对类风湿关节炎的试验已进入IIa期临床阶段。启元生物的JAK1/TYK2抑制剂QY201已在中国获批多项临床试验，针对的适应症包括特应性皮炎、斑秃、银屑病、类风湿关节炎。该药也是启元生物首个进入临床阶段的在研新药。BMS用实力证明了TYK2靶点的成药安全性。目前国内TYK2靶点药物研发仍处于早期阶段，未来如何通过创新式的结构优化、差异化的结构设计来取得更优秀的TYK2抑制剂，成为各大药企努力的方向。国内谁将率先突围，我们拭目以待。参考：1.Bristol Myers Squibb - Bristol Myers Squibb’s Applications for Deucravacitinib for the Treatment of Moderate to Severe Plaque Psoriasis Accepted by U.S. Food and Drug Administration and Validated by European Medicines Agency.2.Jennifer Beecker et al; TYK 2 inhibitors for the treatment of dermatologic conditions: the evolution of JAK inhibitors.doi: 10.1111/ijd.15605.3.Karaghiosoff M, Neubauer H, Lassnig C, et al. Partial impairment of cytokine responses in Tyk2-deficient mice.Immunity 2000; 13: 549–560.封面图来源：123rf推荐阅读第四届“健康中国思南峰会”在沪召开：数字化转型推动医疗健康产业变革【重磅录像】颜宁：“AI在结构生物学中的未达之地”二期临床刚成功，股票就大涨，看了这款mRNA癌症疫苗，我悟了……武田60亿美元买的药，其实是AI设计的干货 | 如何成为一名优秀的BD？这啥CAR-T啊？刚做完一期临床，就卖了40多亿美元...推荐阅读沙利文发布：中国首个白血病领域CAR-T产品NDA受理，掀起商业化新浪潮我们在冬天里欢聚，一起讲述春天的故事！——第二届中国新药领袖闭门交流会成功举办！第四届“健康中国思南峰会”在沪召开：数字化转型推动医疗健康产业变革【重磅录像】颜宁：“AI在结构生物学中的未达之地”首款！FDA批准辉凌制药治疗膀胱癌全新基因疗法二期临床刚成功，股票就大涨，看了这款mRNA癌症疫苗，我悟了……动力学+铁死亡：深势科技首次公开RiDymo™平台管线应用进展武田60亿美元买的药，其实是AI设计的？重磅预告！【药时代奖学金】即将闪亮登场！挖坟老靶点？去年抗新冠，今年抗肿瘤，回顾 CD24「卧薪尝胆」的40年药时代BD高阶研讨会火热报名中！

临床2期引进/卖出临床1期

2022-12-20

·药时代

祐森健恒TYK2别构抑制剂在澳大利亚完成首例受试者给药

Usynova Initiates First-in-Human Phase 1 Clinical Trial of Allosteric TYK2 Inhibitor UA021 in AustraliaUsynova Pharmaceuticals Ltd, a private and clinical stage biotechnology company focused on developing innovative medicines for treatment of cancer and inflammatory diseases, today announced the dosing of first healthy volunteer in Australia in a Phase 1 clinical study of UA021, a potent, selective and allosteric investigational tyrosine kinase 2 (TYK2) inhibitor.“UA021 is an oral small molecule inhibitor that targets the pseudokinase (JH2) domain of TYK2 and has showed superior in vitro and in vivo activities in preclinical studies. The unique PK and superior safety profile of UA021 may provide better in vivo target coverage, and can hopefully translate into differentiated and better efficacy in patients with autoimmune diseases, such as psoriasis and inflammatory bowel disease (IBD). This molecule is ideal for combinational studies for overcoming drug resistance and treatment of hard-to-treat diseases,” commented Shengbin Peng, Ph.D., CSO of Usynova.“UA021 program is an excellent reflection of our R&D effectiveness. It took us approximately 20 months from project initiation, lead identification and optimization to first human dose. We are committed to develop this important molecule in China and globally, and the Phase I clinical study in China will likely occur in first quarter, 2023,” added Tao Hu, Ph.D., CEO of Usynova.The first-in-human Phase 1 trial (ACTRN12622001349730) is designed to evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic effects of UA021. The trial is expected to enroll 64 healthy volunteers in Australia, and a separate Phase I study in China is planned in Q1, 2023.About UA021UA021 is a potent, selective, and orally bioavailable TYK2 inhibitor. It allosterically targets the pseudokinase (JH2) domain of TYK2 with strong selectivity against other members of JAK family. Thus, it is expected to overcome the toxicities caused by active site JAK inhibitors due to their pan-inhibition of JAK family members. UA021 has showed similar or superior in vitro and in vivo activities to other competitors in preclinical studies, and demonstrated excellent safety profile in preclinical toxicity evaluation. It has the potential to achieve better in vivo target coverage and efficacy in patients. UA021 is currently being evaluated in a Phase 1 clinical study in Australia.About TYK2TYK2 is a member of the JAK family including JAK1, JAK2, JAK3 and TYK2. It is a critical component involved in signaling pathways mediated by many pro-inflammatory cytokines such as IL-12, IL-23, and Type 1 interferons. The dysfunction of these cytokines plays a determinant role in the induction of inflammation which is implicated in many immune-mediated disorders such as psoriasis, IBD and other autoimmune diseases.About UsynovaUsynova Pharmaceuticals Ltd, located at Zhangjiang Hi-Tech Park, Shanghai, is a private and clinical stage biotechnology company focused on developing innovative medicines for treatment of cancer and autoimmune diseases. The company has established internal drug discovery platforms of small molecules and biologics. It currently has multiple pipeline products at different R&D stages. UA007, the lead asset of the company is currently in phase II clinical studies for two indications, gouty arthritis and chemotherapy-induced diarrhea (CID). The early clinical POC results of UA007 in both indications were achieved in the ongoing phase II studies. Gouty arthritis is one of the most common diseases in China and globally, and the current treatments often have drug resistance or undesirable side effects. CID is one of the main side effects of cancer chemotherapy, and it is also an important reason for cancer patients to withdraw from chemotherapy. However, there is currently no effective medicine for treatment of CID. In addition to UA007 and UA021, the company also has a few small molecules in late stage preclinical development.祐森健恒TYK2别构抑制剂在澳大利亚完成首例受试者给药祐森健恒生物医药（上海）有限公司（“祐森健恒”）的TYK2别构抑制剂UA021再传捷报，继获得国内临床试验申请受理通知书后，澳大利亚I期临床也进展顺利，于2022年12月19日完成首例健康受试者给药。祐森健恒CSO彭生斌博士表示：“UA021此次给药，标志着公司开发的TYK2小分子别构抑制剂治疗银屑病等自身免疫性疾病进入到临床阶段，彰显了公司在该疾病领域中强大的药物研发实力。后续将根据产品的特点和创新的临床开发策略，加速UA021在全球的开发进程”。祐森健恒CEO胡滔博士强调：“UA021项目顺利且快速在中澳两国同步推进，体现了祐森健恒立足国内、放眼国际的发展决心”。近期，武田（Tekeda）以60亿美元从Nimbus收购了后者完成II b阶段临床的在研TYK2别构抑制剂NDI-034858。这一消息再度点燃业界对TYK2别构位点的热情。祐森健恒的TYK2别构抑制剂在澳洲的一期临床，是中国创新药有能力进军国际主流市场的例证。需要特别指出的是，祐森健恒的UA021项目从立项、确认PCC到首次人体给药，只用了不到20个月。这充分体现了公司科研团队对项目的深刻理解和高效的组织和执行能力。关于UA021UA021是祐森健恒生物医药(上海)有限公司研发的口服小分子TYK2别构抑制剂。临床前研究表明，与同类型其他药品相比，UA021具有更好的药代动力学性质，且在动物毒理实验中表现出很好的安全性，此外， UA021 在临床上有望耐受更高的给药剂量，从而达到更好的治疗效果。这对于需要高剂量给药的IBD、红斑狼疮等疾病的治疗有着重要的意义。关于TYK2TYK2是Janus激酶家族（JAK）的成员，参与细胞因子IL-23、IL-12、I型IFN的信号传导，并介导下游的STAT磷酸化，这一通路机制已被证实是银屑病和其他自身免疫病的重要致病机制。目前已批准上市的活性中心JAK抑制剂，由于靶点选择性差，临床应用中易引起血液毒性等严重副作用，被FDA赋予“黑框警告”。UA021通过分子别构机制特异性抑制TYK2，对JAK家族的其他成员有良好的选择，从而降低因多个JAK 家族成员的抑制而导致的不良反应。其同类药 Deucravacitinib已经在III期临床研究中获得很好的疗效并获得FDA批准上市，国内尚无同类产品上市，UA021有望成为同领域中有差异化和竞争力的药物。关于祐森建恒生物医药（上海）有限公司成立于2020年1月。公司聚焦于自身免疫性疾病和癌症两大领域，立足于解决未满足的临床需求，开发具有自主知识产权的一类新药。公司拥有国内一流的管理团队，具备顶尖的研发实力。创始人及核心团队成员来自跨国药企、国内CRO龙头企业，在小分子药物、抗体药物研发领域具有深厚的项目积累，尤其是在肿瘤及免疫领域有多年开发经验。公司研发管线丰富，有10多个主要在研产品，包括First-in-class项目。点击这里，更多了解祐森健恒！

临床结果临床1期

2022-12-14

·生物制药小编

NSCLC四大类靶向药物的分子耐药机制

精准医学的出现为非小细胞肺癌(NSCLC)的治疗带来了曙光，通过遗传和表观遗传线索进行靶向治疗，扩大了晚期NSCLC患者的选择范围。NSCLC患者的肿瘤致癌基因已被逐一发现，包括表皮生长因子受体(EGFR)、间充质淋巴瘤激酶(ALK)和受体酪氨酸激酶ROS原癌基因1(ROS1)等。靶向调节NSCLC肿瘤生长和发展的关键基因介导的信号通路的抗体和小分子抑制剂有望提高患者的存活率和生活质量。FDA批准的靶向药物已有近30种，用于NSCLC激酶抑制剂治疗的主要靶点是EGFR、ALK、ROS1和BRAF、MET和RET (图1)。化疗和靶向治疗已显著改善了NSCLC患者的预后。然而，由于癌症驱动因素的基因改变而产生的耐药性给治疗转移性NSCLC患者带来了巨大的挑战。本文就NSCLC靶向经典靶点的四大类药物的分子耐药机制做一个简要介绍，旨在为后续药物设计提供新思路。图1. 与NSCLC靶向药物相关的基因和通路EGFR TKIs的耐药机制由于超过60%的NSCLC细胞表达EGFR，它已成为治疗这些恶性肿瘤的重要靶点。外显子20的T790M突变存在于50%-60%对第一代EGFR TKI耐药的个体中，如erlotinib。T790M突变所致的蛋白质空间结构异常使第一代TKI不能很好的结合到EGFR酪氨酸激酶区，阻止了TKI发挥抑制EGFR通路的作用；此外，T790M突变增加了EGFR酪氨酸激酶与ATP的亲和力，因此T790M突变导致了对第一代EGFR-TKI的耐药。其他的继发性常见突变为D761Y、L747S和T854A。它们降低了突变的EGFR对EGFR-TKI的敏感性。然而，它们是如何产生耐药性的机制尚不清楚。一种可能性是，这些次级耐药突变改变了EGFR的构象以及它与TKI的相互作用方式。其他耐药机制包括MET基因扩增，包括EGFR扩增和PIK3CA基因突变，以及SCLC 的转化(图2)。小细胞肺癌(SCLC)在组织学上可转化为非小细胞肺癌(NSCLC)的比例高达14%，这种转化通常伴随着对原始TKI的耐药性。图2. 对EGFR-TKIs耐药的机制和频率在最近对Flaura试验的回顾分析中，研究了EGFR外显子20的C797S突变在EGFR突变的晚期非小细胞肺癌中获得性耐药的机制。当使用axitinib作为一线治疗时，该突变发生的频率为7%。当使用一线osimertinib和二线axitinib治疗后，其占比10%-26%。Osimertinib-EGFR共价链被EGFR(C797S)突变断开。通过抑制它们与EGFR活性部位的结合，C797S突变还使其他不可逆转的第三代TKI产生交叉耐药性，如roxitinib, omutinib, and nizatinib。MET扩增(15-19%)、PIK3CA(6-7%)、KRAS(3%)和HER2扩增(2-5%)是最常见的获得性耐药机制。旁路通路的激活，通过持续激活EGFR下游的信号通路，包括由MAPK、STAT和PI3K-Akt介导的信号通路，可导致oxitinib耐药。ALK TKIs的耐药机制有三种不同类型的ALK基因突变：点突变、扩增和重排(ALK-R/ALK-A)。大多数ALK基因突变采取易位到另一个配对基因的形式，在癌症中创造了过度表达的融合癌基因。2002年首次发现了ALK-A在NB细胞系中的致癌机制。ALK-A已被证明引起结构性激活，只有当SHcC接近ALK受体底物时才能激活SHcC。在第一代crizotinib复发后活检的18例患者中，有4例(22%)发现了ALK TK区域的突变，包括3个新的突变和1个ALK融合基因的扩增。已经鉴定的ALK获得性耐药点突变包括G1269A、C1156Y、I1171T/N/S、S1206C、E1210K、L1152P/R、V11180L、G1128A、F1174V和L1196M。旁路信号通路的激活，如转录辅助调节因子YAP的激活、EGFR信号、KIT扩增、IGF-1R通路、MAPK扩增、BRAF(V600E)突变和MET扩增是ALK-TKIs耐药机制的另一个组成部分。在使用下一代ALK抑制剂复发的患者中，15%的肿瘤样本中存在MET扩增，而在使用第二代抑制剂或lorlatinib的患者中，肿瘤活检标本中MET扩增的比例分别为12%和22%。MET的改变是ALK阳性NSCLC的一种普遍的功能耐药机制。大量研究表明，当第一代ALK抑制剂治疗NSCLC患者失败时，第二代药物alectinib、ceritinib、brigatinib和ensatinib可能比化疗更有效。在接受第二代ALK抑制剂治疗的患者中，G1202R突变是最常见的继发性耐药ALK突变，出现在接受ceritinib、alectinib和brigatinib治疗的患者中的比例为21%、29%和43%。ROS1抑制剂的耐药机制通过临床前和临床的研究，已经确定了使ROS1融合阳性癌症对ROS1 TKI产生耐药性的ROS1激酶的点突变。ROS1激酶域的点突变，如D2033N、G2032系列、L2026M、L2155S和S1986F/Y，可导致对crizotinib的获得性耐药性。在一项研究中，在不同时间点分别进行分析的42例crizotinib和28例lorlatinib活检中，分别有38%和46%的样本发现了ROS1突变。近三分之一的患者具有最常见的突变ROS1(G2032R)。另外还有D2033N(2.4%)、S1986F(2.4%)、L2086F(3.6%)、G2032R/L2086F(3.6%)、G2032R/S1986F/L2086F(3.6%)等ROS1突变。由于D2033N突变导致ROS1的激酶铰链区从天冬氨酸变为天冬酰胺(在ATP结合位点内)，crizotinib表现出显著的体外耐药性。ROS1激酶域突变L2026M与G2032R相似，它通过改变ROS1抑制剂结合口袋的位置而导致对crizotinib的耐药。此外，激酶结构域上的S1986F/Y替换阻断了重要的激活位点，从而提高了激酶的活性。通过突变或拷贝数增加，其他RTK或下游MAPK通路效应器被牵连到ROS1外在耐药机制中。MAPK系统重新激活是一种重要的耐药机制。KRAS、NRAS、EGFR、HER2、MET、KIT、BRAF和MEK是参与该通路的下游或旁路介质。Kit和catenin突变以及HER2介导的旁路信号被发现是非ROS1的主要耐药途径。数据还表明，RAS家族成员的激活可以产生对ROS1抑制剂的耐药性。在临床中，KRAS(G12D)和BRAF(V600E)突变与crizotinib治疗有关，而NRAS（Q61K）与entrectinib治疗有关。BRAF抑制剂的耐药机制大约50%的BRAF突变是BRAF(V600E)。其他典型的BRAF突变是BRAF(D594G)和BRAF(G469A/V)突变，分别存在于35%和6%的BRAF突变NSCLC患者中。V600E突变而不依赖RAS，而是通过与K507建立盐桥来稳定BRAF的活性构象，从而极大地提高了BRAF的活性。BRAF(V600E)突变导致其单体形式的结构性BRAF激活，从而促进MEK-ERK信号下游。虽然BRAF(V600)基因靶向药物vemurafenib和dabrafenib作为单一疗法在临床上是有效的，但MEK抑制剂的加入极大地改善了治疗效果。BRAFi和MEKi联合用药优于单一用药，ORR率提高到67%，中位PFS提高到10.2个月。治疗上也需要对非BRAF(V600E)突变有效的BRAF抑制剂，这种突变存在于大约50%的BRAF突变的NSCLC中。BRAF非依赖的c-Jun信号传导或全长BRAF (V600E)缺失引起的自分泌激活导致EGFR信号传导增加，这是vemurafenib连续治疗BRAF(V600E)突变的NSCLC的获得性耐药机制。值得注意的是，已表明第二代BRAF抑制剂(BRAFi)或BRAF和MEK抑制剂的组合可以防止因产生BRAF(V600E)剪接变体(例如PLX8394)而产生的耐药性。CRAF激酶的表达是Montagut等人发现的耐药机制之一。根据这项研究，CRAF蛋白含量高的突变细胞降低了药物的生物利用度。不幸的是，大多数NSCLC患者将在使用BRAF和MEK抑制剂治疗后一年内经历疾病进展。根据临床前和临床数据，除了BRAF突变外，耐药机制还包括旁路通路的激活，包括PI3/AKT/mTOR，以及由于上游或下游变化而变得无效的MAPK信号的恢复(图3)。重新激活MAPK通路信号的BRAFi耐药机制也已经被研究。据报道，PDGFR和EGRF等RTK的过度表达或上调是导致RAF抑制剂耐药的第一个因素。由于这些修饰刺激RAS并激活CRAF-MEK-ERK信号，癌细胞的增殖不依赖于BRAF(V600E)。RAS突变，其功能类似于RTK改变，被确定为RAF抑制剂耐药的第二个因素。一旦癌细胞具有大量的活性RAF，载药的BRAF(V600E)就会与CRAF二聚化并激活其催化活性，这被称为RAF抑制剂的悖论效应。因此，BRAFi的下一迭代抑制剂仍需继续优化和开发。图3. BRAF耐药机制和突变概率小编小结总之，精准靶向药物为癌基因驱动的NSCLC患者提供了实质性的益处，但癌症患者可能会通过多种途径产生药物耐药性。因此要为每个患者进行定制化的靶向治疗，需要在分子水平上评估它们的特定耐药机制。参考文献Non-Small Cell Lung Cancer Targeted Therapy: Drugs and Mechanisms of Drug Resistance.Molecular testing and targeted therapy for non-small cell lung cancer: current status and perspectives.Understanding and targeting resistance mechanisms in NSCLC.

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