PIK3CA突变的药物研究进展
Research Progress on Drugs Targeting PIK3CA Mutations
DOI: 10.12677/acm.2025.1572145, PDF, HTML, XML,   
作者: 李 彤, 夏雪敏:西安医学院研究生工作部,陕西 西安;白 俊*:陕西省人民医院肿瘤内科,陕西 西安
关键词: PIK3CA突变PI3K/AKT/mTOR信号通路PI3K抑制剂靶向治疗PIK3CA Mutation PI3K/AKT/mTOR Signaling Pathway PI3K Inhibitors Targeted Therapies
摘要: PI3K/AKT/mTOR通路是细胞内一个重要的信号传导通路,参与调控细胞的增殖、生长、代谢和存活等多种生物学过程,在多种癌症中发生突变或扩增,包括乳腺癌、胃癌、卵巢癌等。该信号通路在癌细胞存活、血管生成和转移中起重要作用。PI3Kα是该通路中一种关键的脂质激酶,具有催化和抑制两个亚基,其中PIK3CA是编码p110α催化亚基的基因,是一种在多种亚型乳腺癌中高度突变的癌症蛋白,且PI3Kα信号转导失调通常与肿瘤发生和耐药性有关,因此,靶向PIK3CA突变的药物研发是目前乳腺癌精准治疗的热门方向。针对PI3K的选择性抑制剂已经被成功开发,PI3Kα特异性抑制剂阿培利司(Alpelisib)已被FDA批准作为PIK3CA突变乳腺癌的治疗药物。然而由于毒性问题未能有效解决,该药物的应用仍有限制。在这篇综述中,我们将总结PIK3CA突变导致乳腺癌耐药机制及靶向PIK3CA突变的药物研发的安全性问题和最新进展,以期对PIK3CA突变患者提供更有效的个体化治疗。
Abstract: The PI3K/AKT/mTOR pathway is a critical intracellular signaling cascade that regulates diverse biological processes, including cell proliferation, growth, metabolism, and survival. This pathway undergoes mutations or amplifications in various cancers, such as breast cancer, gastric cancer, and ovarian cancer. It plays a pivotal role in the survival, angiogenesis, and metastasis of cancer cells. PI3Kα serves as a key lipid kinase within this pathway, consisting of two subunits: catalytic and regulatory. Notably, PIK3CA is the gene encoding the catalytic subunit p110α, which is frequently mutated in multiple subtypes of breast cancer. Dysregulation of PI3Kα signaling is often associated with tumorigenesis and drug resistance. Consequently, the development of drugs targeting PIK3CA mutations has become a prominent focus in the precision treatment of breast cancer. Selective inhibitors targeting PI3K have been successfully developed, and the PI3Kα-specific inhibitor Alpelisib has been approved by the FDA for the treatment of PIK3CA-mutated breast cancer. However, the clinical application of these drugs remains limited due to unresolved toxicity issues. In this review, we summarize the mechanisms underlying drug resistance in PIK3CA-mutated breast cancer, as well as the safety concerns and recent advancements in the development of PIK3CA-targeted therapies. Our aim is to provide insights into more effective personalized treatment strategies for patients harboring PIK3CA mutations.
文章引用:李彤, 夏雪敏, 白俊. PIK3CA突变的药物研究进展[J]. 临床医学进展, 2025, 15(7): 1440-1449. https://doi.org/10.12677/acm.2025.1572145

1. 引言

PIK3CA (磷脂酰肌醇4,5-二磷酸3-激酶催化亚基α,phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)突变与PI3K/AKT/mTOR信号传导通路的异常激活有关[1]。PI3K/AKT/mTOR通路在细胞生长、存活和增殖中起着至关重要的作用,该通路的异常激活影响细胞周期、生存、代谢及基因组不稳定性,并促进肿瘤微环境的形成,例如血管生成和炎性细胞募集[2]。其异常激活与肿瘤的发生、发展密切相关,尤其在包括乳腺癌在内的多种恶性肿瘤中。当编码基因发生突变时,可导致PAM信号通路异常激活[3],刺激肿瘤的增殖、转移和侵袭,并且与治疗应答不佳、预后不良、或内分泌治疗耐药相关[4]。因此,PIK3CA突变可作为肿瘤靶向治疗的重要指标。

2. PIK3CA与肿瘤发生

2.1. PIK3CA突变介导的PI3K/AKT/mTOR信号通路

PI3K是脂质激酶,分为三个不同的类别,I类参与细胞信号传导,而II类和III类调节细胞运输。I 类PI3K是由一个p85调节亚基和一个p110催化亚基(p110α、p110β、p110γ或p110δ)组成的异二聚体,调节亚基p85由PIK3R1基因编码,催化亚基p110α由PIK3CA基因编码[5]

PIK3CA基因定位于3q26.3,长34 kb,包含21个外显子,编码1068种氨基酸,组成长124 kD的蛋白[6]。多数情况下,该基因处于非激活的状态,一旦基因发生突变,PIK3CA被异常地激活,导致蛋白过度表达,从而促使细胞发生癌变。研究表明PIK3CA基因在多种癌症中发生突变或扩增,如结直肠癌(CRC)、乳腺癌、肺癌、胃癌、前列腺癌和宫颈癌,且在乳腺癌中最为常见,其中超过80%的突变发生在螺旋区(Helical)和激酶区(Kinase)这两个热点区域,经典突变位点为:p110α 9号外显子的E545K、E542K (螺旋形域)及20号外显子的H1047R、H1047L (激酶结构域),其中H1047R突变发生率最高[7]。螺旋形域突变(如E545K和E542K)通过Ras-GTP激活PI3K;激酶结构域突变(如H1047R)通过p85激活PI3K。此外,E545K突变可直接结合胰岛素受体底物1 (IRS1)蛋白调控AKT信号通路活性;而H1047R突变可导致其构象变化,从而促进PI3K磷酸化PIP2激活PI3K-Akt信号通路。

PI3K/AKT/mTOR通路由磷脂酰肌醇3-激酶(PI3K)通过信号级联传递多种细胞外刺激。在正常生理状态下,细胞膜上的生长因子受体或G蛋白偶联受体被来自细胞外的配体激活后,PI3K将磷脂酰肌醇(4,5)-二磷酸(PIP2)转化为磷脂酰肌醇(3,4,5)-三磷酸(PIP3),PIP3的生成介导PDK1和PDK2磷酸化并激活AKT进而磷酸化众多底物,包括TSC1/2 (tuberous sclerosis complex 1/2),从而调节细胞生长和存活所需的下游信号通路[2]

2.2. PIK3CA基因突变导致乳腺癌耐药机制

PIK3CA体细胞突变发生在30%~50%的早期原发性乳腺癌以及转移性乳腺癌中[8],一项meta分析纳入了1929例包含所有亚型以及BC的早期和转移期患者,发现PIK3CA突变是一个独立的不良预后因素。在所有乳腺癌亚型中,PIK3CA突变的患病率在25%到40%之间,最高在HR+/HER2− BC(激素受体阳性、人表皮生长因子受体2阴性的乳腺癌患者)中。SAFIR02研究[9]显示,在HR+/HER2−晚期乳腺癌中携带PIK3CA突变的患者易出现化疗耐药,预后更差;PALOMA3研究[10]也提示存在PIK3CA突变的HR+/HER2−晚期乳腺癌患者总生存期(OS)较PIK3CA野生型患者更短。在TNBC中,大多数PIK3CA突变存在于原发性TNBC中,晚期TNBC的突变率可能会增加,ER+乳腺癌中观察的PIK3CA突变率很高,该乳腺癌会复发、失去ER表达并成为继发性TNBC,同时保持PI3K的高激活率。此外,PIK3CA突变还与CDK4/6抑制剂耐药、抗HER2治疗耐药及化疗耐药相关,有研究提出HR+/HER2−乳腺癌细胞对CDK4/6抑制剂耐药是通过PI3K-Akt-mTOR信号通路的上调[11]。由此看出,PIK3CA突变不仅是乳腺癌耐药的重要标志,还可能成为逆转耐药性的关键靶点。

3. PIK3CA抑制剂的研发

鉴于PI3K在癌症中的关键作用,在过去的20多年里一直是相关研究和药物开发的重要靶点。PI3K抑制剂可分为三大类:泛PI3K抑制剂(Pan-PI3Ki)、PI3K亚型选择性抑制剂(IS PI3Ki)和PI3K/mTOR双重抑制剂(PI3K/mTORi) [12]

3.1. 泛PI3K抑制剂

目前FDA已经批准上市5类PI3K抑制剂,都属于Pan-PI3Ki,其中包括用于治疗乳腺癌的PI3Kα抑制剂阿培利司(Alpelisib)和用于治疗血液疾病的PI3Kδ抑制剂厄布利塞(Umbralisib)、度维利塞(Duvelisib)、库潘尼西(Copanlisib)和艾德拉尼(Idelalisib) [13]。泛PI3K抑制剂(Pan-PI3Ki)抑制PI3KI类异构体的所有亚型的激酶活性:PI3Kα、PI3Kβ、PI3Kγ和PI3Kδ,分别由PIK3CA、PIK3CB、PIK3CG和PIK3CD编码,因此,这些药物通常对产生高水平PIP3的肿瘤有效,而不考虑PI3K基因的类型或PTEN的改变[14]。四种亚型与多种生理功能相关,如葡萄糖代谢、炎症和免疫等,因此泛PI3K抑制剂不可避免地增加了安全风险,特别是代谢相关不良事件的高发生率,如高血糖[15],绝大数泛PI3K抑制剂因毒副作用被迫终止研发,目前只有库潘尼西(Copanlisib)在2017年被FDA批准用于治疗成人复发性滤泡性淋巴瘤。为减少毒性,随后开发出了具有亚基选择性的抑制剂。

3.1.1. PX-866

PX-866是一种口服的、不可逆的泛PI3K抑制剂[16],是wortmannin(一种天然呋喃类固醇代谢物)的半合成衍生物,是PI3K家族的共价非特异性抑制剂[17]。多项实验表明,PIK3CA突变或PTEN缺失预示着对PX-866的阳性反应,而致癌基因Ras突变是耐药的主要标志[18]。PX-866已获批临床试验,在多种癌症类型中表现出良好的耐受性和潜在疗效,在联合给药治疗方面,它逆转了对表皮生长因子受体(EGFR)抑制剂的耐药,增加了顺铂的抗肿瘤作用[19]

3.1.2. BKM120

BKM120作为一种泛PI3K抑制剂,通过可逆性抑制ATP,表现出对PIK3CA致癌突变的优先抑制[20]。一项I期剂量递增研究在晚期实体瘤中发现了良好的耐受性[21]。然而,其他试验显示,PI3K途径单药治疗PIK3CA/AKT/PTEN改变的转移性乳腺癌的疗效有限[22]。BKM120与西妥昔单抗(anti-EGFR)的联合治疗在复发/转移性头颈部鳞癌(R/M SCCHN)中具有有效的抗肿瘤作用[23]

3.1.3. 库潘尼西(Copanlisib)

泛PI3K抑制剂库潘尼西(BAY 80-6946/Copanlisib)能更有选择性地靶向αδ亚型[24]。PIK3CA激活突变或HER2过表达时,Copanlisib在乳腺癌细胞中的抗增殖活性更高[24]。在单药治疗中,一项I期临床试验发现Copanlisib具有出色的抗肿瘤活性[25]。联合治疗中,一项III期临床试验证实,联合利妥昔单抗(anti-CD20)可改善复发性惰性非霍奇金淋巴瘤(iNHL)的PFS (progression-free survival,无进展生存期) [26]。Copanlisib是唯一被FDA批准用于治疗复发性滤泡性淋巴瘤(follicular lymphoma, FL)的泛PI3K抑制剂[27]。除此之外,也有临床前研究[28]发现,在子宫内膜癌PDX模型中小鼠被Copanlisib处理后,具有PIK3CA基因突变的小鼠模型受到显著抑制。在一项复发性子宫内膜癌的Ⅱ期临床试验(NCT04750941)中,Copanlisib对PIK3CA突变癌症患者的mPFS (Median PFS,中位无进展生存期)为2.8个月[29]

3.1.4. Izorlisib

CH5132799/Izorlisib基于结构的药物设计方法合成,利用PI3Kα的同源性模型进行分子设计[30]。在临床前模型中,无论是单独使用还是联合使用,Izorlisib在体外激酶检测、体外肿瘤和体内小鼠异种移植模型中都表现出对PIK3CA突变的敏感性[31]。有研究确定每日两次48 mg为RP2D (Recommended Phase II Dose,II期推荐剂量),在该剂量下,该药表现出良好的耐受性和临床活性,具有低毒性及与其他靶向治疗联合的潜力[32]

3.1.5. ZSTK474

ZSTK474是一种泛PI3K抑制剂[33],体外研究表明,ZSTK474对E542K、E545K、H1047R热点突变和野生型PI3Kα都有很强的活性[34]。目前,有研究发现与单独的放射或药物治疗相比,ZSTK474和X射线结合具有更大的治疗潜力[35]

3.2. PI3K亚型选择性抑制剂(IS PI3Ki)

PI3Kα特异性抑制剂是PI3K催化亚基p110α I类的一组选择性口服抑制剂。其他亚基可以被抑制,但该类的所有成员对PI3Kβ的作用都显著降低,以限制共同的副作用风险[36]。特异性PI3K抑制剂(IS PI3Ki)已被确定用于靶向依赖PI3Kα、PI3Kβ、PI3Kγ或PI3Kδ亚型的癌症类型。通常,由于在非癌细胞中多种PI3K亚型的表达减少,这些药物显示出更广泛的治疗指数和更小的脱靶毒理学效应[7]。值得注意的是,PI3Kα和PI3Kβ亚型在所有组织中普遍表达,突变多发生于实体瘤,而PI3Kγ和PI3Kδ亚型主要局限于白细胞,主要针对炎症、血液疾病和自身免疫性疾病[37]

3.2.1. 阿培利司(Alpelisib)

阿培利司(BYL719/Alpelisib)是一种针对PI3Kα亚型具有靶向选择性的强效特异性口服药物,其抗PI3Kα的效力是其他亚型的50倍[38],经FDA批准与氟维司群联合使用,在激素受体阳性、人表皮生长因子受体2阴性HR+/HER2−、PIK3CA突变的晚期或转移性乳腺癌患者中显示出显著的临床益处[7]。一项Ⅲ期临床试验SOLAR-1 (NCT02437318)的研究共纳入572例既往接受过内分泌治疗的HR+/HER2−晚期乳腺癌患者,其中341例患者存在PIK3CA突变,169例PIK3CA阳性的患者接受Alpelisib + 氟维司群,172例PIK3CA阳性的患者使用安慰剂 + 氟维司群,在PIK3CA突变癌症患者队列中,Alpelisib + 氟维司群组和安慰剂 + 氟维司群组的中位无进展生存期(mPFS)分别为11.0月vs 5.7月,12个月PFS率为46.3% vs 32.9%,针对未携带PIK3CA突变的乳腺癌患者Alpelisib未显示出治疗效果[39]

3.2.2. WX-037

WX-037是I类PI3K抑制剂。在临床前研究中,WX-037对PIK3CA突变或PTEN缺失的细胞和肿瘤的敏感性增加[40]。然而,其在实体肿瘤中作为单一药物和与WX-554 (MEK抑制剂)联合的I期试验因商业原因而终止(NCT01859351)。

3.2.3. 他塞利西布(Taselisib)

他塞利西布(Taselisib)是PI3Kα/γ抑制剂,对p110α、p110γ具有同等抑制作用[41]。Taselisib的首次人体研究涉及34例实体瘤患者,观察到的不良反应与其他PI3K抑制剂一致,包括高血糖、腹泻、皮疹和口炎,最常见的3级或4级不良事件(AEs)是高血糖(15%)和皮疹(12%) [42],PIK3CA突变肿瘤患者的客观缓解率(ORRs)为36%,而没有已知激活PIK3CA突变患者的ORRs为0% [43],该试验支持Taselisib对PIK3CA突变型癌症具有更高的效力[44]。一项新的I期临床研究(NCT01296555)旨在发现单药Taselisib是否对多种PIK3CA突变肿瘤具有活性。

3.2.4. Inavolisib

Inavolisib是新一代PI3Kα抑制剂,可以高选择性抑制PI3Κα,并且能特异性降解PI3Κα突变蛋白的双重作用机制,能有效地抑制突变型PI3K通路信号传导和细胞生存能力,且避免抑制野生型信号传导所致的全身性副作用[45]。Inavolisib已进入临床III期INAVO120试验,在涉及PIK3CA突变的HR+/HER2−晚期或转移性乳腺癌的I/Ib期研究中,其与哌柏西利(Palbociclib)和内分泌治疗(ET)联合治疗显示出可控的安全性,并且具有初步的抗肿瘤活性[46] (NCT03006172)。

3.2.5. CYH33

CYH33是一种高选择性PI3Kα抑制剂。在针对实体瘤患者的第一项人体Ia期研究之后,CYH33已进入II期临床试验,观察到其在PIK3CA突变实体瘤中抗肿瘤效果显著[47]。正在进行的临床试验在尝试联合治疗,包括CYH33与奥拉帕尼联合治疗晚期实体瘤(NCT04586335),以及与内分泌治疗联合治疗晚期HR+/HER2−乳腺癌(NCT04856371)。

3.2.6. RLY-2608

RLY-2608是PI3Kα变构突变选择性抑制剂。RLY-2608对PI3Kα H1047R的抑制不是ATP竞争性的,其抑制不仅对PI3Kα H1047R有高选择性,而且对PI3K亚型也有很高的选择性[48]。RLY-2608克服了PI3Kα抑制剂部分不良反应的限制,如最突出的高血糖,在PIK3CA突变异种移植模型中抑制肿瘤生长,对胰岛素的影响可以忽略不计[48]。在2例诊断为PIK3CA突变的晚期HR+乳腺癌患者中,RLY-2608产生了客观的肿瘤反应[48]。RLY-2608已进入临床试验阶段,并正在参加其首次人体研究,作为单药或与氟维司群联合治疗晚期实体瘤(NCT05216432)。

3.2.7. LOXO-783

LOXO-783是一种有效的靶向PI3Kα H1047R突变的高选择性抑制剂。LOXO-783在H1047R驱动的乳腺癌临床前模型中表现出显著的抗肿瘤作用,并且不会引起高血糖或其他与更广泛的PI3K抑制剂相关的常见毒性[49]。除了其有效性和安全性外,LOXO-783还具有较高的口服生物利用度和穿过血脑屏障的能力,扩大了其在治疗中枢神经系统癌症方面的潜在用途[13]。该化合物在携带PI3Kα H1047R突变的HR+和三阴性乳腺癌(TNBC)中,可协同增强现有疗法的抗肿瘤作用,目前,LOXO-783及其联合疗法正在I期临床试验中进行评估(PIKASSO-01, NCT05307705)。

3.2.8. STX-478

STX-478是一种突变选择性PI3Kα抑制剂。STX-478选择性抑制PI3Kα激酶结构域的所有突变形式,包括常见的H1047R突变,对E542K和E545K螺旋结构域突变体的选择性较弱[50]。STX-478在无胰岛素抵抗的PI3Kα突变肿瘤的临床前模型中表现出优异的抗肿瘤效果,并且与氟维司群和细胞周期蛋白依赖性激酶(CDK4/6)抑制剂联合使用可实现持久稳定的肿瘤消退[49]。目前,STX-478正在进行I/II期临床试验(NCT05768139)。

3.3. PI3K/mTOR双重抑制剂

除了前两种类型,PI3K/mTOR双重抑制剂也正在开发当中,其对所有PI3K亚型以及mTOR都有效,会造成PI3K/AKT/mTOR信号通路的三个关键交叉点的抑制。由于大多数已进入实体瘤临床试验的p110α抑制剂以治疗剂量抑制突变型和野生型p110α,这些药物诱导急性胰岛素抵抗,导致严重的高血糖,进而导致严重的高胰岛素血症[50]。当针对PI3K/mTOR进行双重抑制治疗癌症时,关键的考虑因素是如何控制对全身代谢的靶向毒性,这些剂量限制性毒性阻止肿瘤组织中足够的靶标参与以维持通路抑制。事实上,基于PI3K/mTOR通路在细胞增殖、组织生长、代谢和其他生理功能中所起的各种作用,许多这些对PI3K/mTOR通路抑制剂有效治疗的相关毒性是可以预料到的。尽管PI3K抑制剂的研究和开发非常广泛,但在患者的临床治疗过程中观察到的药物相关毒性已成为其发展的重大障碍,这种毒性主要是由于这些抑制剂靶向不同的PI3K亚型,结合了靶标和脱靶效应[13]。泛抑制剂阻断所有I类PI3K亚型,受到广泛的脱靶效应的限制,双PI3K/mTOR抑制剂甚至表现出更广泛的毒性,因此异构体特异性PI3K抑制剂的出现提供了一种实现最大抑制剂量同时避免过度脱靶毒性的方法。目前得到FDA批准的抑制剂都属于前两种类型,其中乳腺癌靶向药物Alpelisib因其显著的药效,被广泛应用于临床。

4. 资料与方法

4.1. 文献检索

通过中英文数据库系统检索PIK3CA抑制剂相关文献,中文检索策略如下:数据库来源:系统检索以下中英文数据库(检索时间截止至2024年6月)。中文数据库:中国知网(CNKI)、万方数据库、维普期刊网(VIP);

英文数据库:PubMed、Embase、Cochrane Library、ClinicalTrials.gov。检索词采用主题词与自由词结合的方式设计:

中文检索式:

("PIK3CA突变" OR "PI3Kα" OR "磷脂酰肌醇3激酶") AND ("抑制剂" OR "靶向治疗") AND ("临床试验" OR "药物开发")

英文检索式(用于英文数据库):

("PIK3CA mutation" OR "PI3K alpha") AND ("inhibitor" OR "targeted therapy")

AND ("clinical trial" OR "drug development")

4.2. 文献筛选流程

纳入标准:研究类型:PIK3CA抑制剂的基础研究或临床研究(I~III期)。

研究对象:明确报道PIK3CA突变肿瘤模型或患者数据。

数据完整性:需包含药效或毒性数据。

排除标准:非肿瘤研究、综述/个案报告(病例数 < 10)。

未设置对照组或未明确突变状态。

重复发表或数据不全的会议摘要。

5. 小结与展望

PI3K/AKT/mTOR是肿瘤发生的经典通路,具有重要的生理功能,其在癌症中的过度激活为靶向癌症治疗提供了许多靶点,特别是最常见的致癌基因PIK3CA,随着基因检测技术和靶向药物的不断发展,PIK3CA基因突变及其抑制剂的研究在乳腺癌精准治疗中将发挥越来越重要的作用。所有乳腺癌亚型都有自己的代谢途径,因此更好地了解每种亚型对这些药物耐药的具体机制将为PIK3CA靶向治疗的优化提供科学依据。尽管PI3K在肿瘤发生中起着核心作用,但仅观察到适度的抗肿瘤活性,抑制PI3K是抗肿瘤治疗的重要靶点,但泛PI3K抑制剂具有某些靶向相关毒性,在过去的几十年里,pan-PI3Ki和双PI3K/mTORi不仅显示出有限的疗效,而且还伴有明显的副作用。

传统pan-PI3K抑制剂与泛PI3K抑制剂(如Buparlisib、Copanlisib)通过抑制所有I类PI3K亚型(α/β/γ/δ)阻断下游信号,但缺乏突变选择性。但其具有毒性显著、疗效受限以及耐药机制复杂的临床局限性,而新一代突变选择性抑制剂既能靶向结合PIK3CA突变体(如H1047R、E545K),减少对正常组织的毒性,又具备与其他药物联合治疗提高临床效果的潜力(见表1)。因此,目前的重点是IS PI3Ki的开发,与传统的pan-PI3Ki和双PI3K/mTORi相比,在很大程度上表现出更好的靶点特异性和毒性谱,同时最大限度地降低耐药风险和不良事件的发生。但PI3Ki发挥的机制尚未完全阐明,需要进一步的研究,设计基于不同结合位点的新型PI3K抑制剂无疑将提高特异性,降低IS PI3Ki的毒性。并且将PI3K抑制剂与其他药物联合使用可能比单药治疗更有效,PI3K抑制剂与其他抗肿瘤药物如化疗药物、免疫疗法和光子学(放射疗法)的联合治疗是未来研究的重要方向之一。特别是PI3Kα抑制剂所带来的高毒性等副作用也成为应用于临床所面临的巨大挑战,对于PI3K抑制剂来说,减少毒副作用,提高安全性是首要任务。通过不断完善检测方法、优化治疗方案,我们有望在不久的将来实现对PIK3CA基因突变患者更为有效的个体化治疗,显著提高患者的生存率和生活质量。

Table 1. Clinical comparison of Pan-PI3K inhibitors vs. mutation-selective inhibitors

1. PI3K泛抑制剂与突变选择性抑制剂临床应用对比

特性

Pan-PI3Ki (如Buparlisib)

突变选择性抑制剂(如Alpelisib)

靶点

抑制所有PI3K亚型(α/β/γ/δ)

仅靶向PI3Kα突变体

疗效

广谱但疗效受限(IC50较高)

突变肿瘤中响应率提升

毒性

肝毒性、免疫抑制(γ亚型相关)

高血糖(α亚型特异性)

耐药机制

多通路代偿(如MAPK激活)

突变位点二次突变(如Q546K)

NOTES

*通讯作者。

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