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   复旦学报(医学版)  2020, Vol. 47 Issue (3): 439-447, 455      DOI: 10.3969/j.issn.1672-8467.2020.03.021
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KRAS基因突变及靶向药物的研究进展
卞赟艺  (综述), 杨晓冬 , 詹成 , 姚光宇 , 毕国澍 , 范虹  (审校)     
复旦大学附属中山医院胸外科 上海 200032
摘要:Kirsten大鼠肉瘤病毒癌基因(Kirsten rat sarcoma viral oncogene,KRAS)突变是多种肿瘤中最常见的致癌因素之一,会导致KRAS的持续活化,进而促使细胞增殖癌变。多年来针对KRAS基因突变的靶向药物一直是研究的热点,但至今仍未能研发出有效针对KRAS基因突变的临床药物。目前靶向KRAS的研究主要通过直接抑制突变的KRAS基因、改变膜定位、靶向KRAS效应信号通路及抑制KRAS突变协同致死基因等机制。本文即对KRAS基因突变肿瘤靶向治疗药物的研究进展进行简要综述。
关键词KRAS基因    基因突变    直接抑制    靶向治疗    
Progress in pharmacological strategies targeting KRAS gene mutated cancers
BIAN Yun-yi , YANG Xiao-dong , ZHAN Cheng , YAO Guang-yu , BI Guo-shu , FAN Hong     
Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Abstract: Kirsten rat sarcoma viral oncogene (KRAS) mutation is one of the most common carcinogenic factors in a variety of tumors, which leads to the continuous activation of KRAS, while it in turn promotes cell proliferation and drives tumorigenesis.Although the exploration of targeted drugs targeting KRAS gene mutations has been a hot research topic for decades, it has not yet been developed to discover clinically effective drugs for KRAS gene mutations.Currently, the mechanisms of targeted therapy for KRAS gene mutation are mainly inhibiting the mutated KRAS genes directly, changing the KRAS membrane localization, inhibiting KRAS signaling pathways, and inhibiting KRAS mutant synergistic lethal genes.Here, we briefly review the progress of pharmacological strategies targeting KRAS mutated cancers.
Key words: KRAS gene    gene mutation    direct inhibition    targeting therapy    

RAS蛋白是一类鸟嘌呤核苷酸结合蛋白,具有GTP水解酶活性,当其与GDP结合时,处于非激活状态(关),而与GTP结合时被活化(开)。鸟嘌呤核苷酸转换因子(guanine nucleotide exchange factors, GEFs)促进GTP与RAS结合,继而激活多条信号通路,如RAF-MEK-ERK, PI3K-AKT-mTOR和Ral-GDS等,调节肿瘤的生长、增殖、分化、和凋亡等生命过程。Kirsten大鼠肉瘤病毒癌基因(Kirsten rat sarcoma viral oncogene, KRAS)是RAS家族中最重要的基因,且KRAS突变是多种肿瘤中最常见的致癌因素之一。KRAS一旦发生突变,就会丧失GTP水解酶活性,进而持续活化,促使细胞持续增殖而癌变。KRAS在胰腺导管腺癌(pancreatic ductal adenocarcinoma, PDAC)中的突变率最高,达97%,其次为结直肠癌、多发性骨髓瘤和肺癌,分别为52%、42%和32%[1]KRAS基因突变的最常见方式是点突变,常见的突变形式有KRAS-G12D突变(41%)、KRAS-G12V(28%)和KRAS-G12C(14%)突变[2]。在非小细胞肺癌(non-small cell lung cancer, NSCLC)中,最常见的是G12C点突变[3]。研究人员一直在寻找能够干扰KRAS与GTP结合的药物,以阻断突变型KRAS基因的致癌作用,但由于KRAS蛋白结构的特殊性,至今为止,临床上尚无有效治疗KRAS突变肿瘤的药物。目前靶向KRAS基因突变的机制主要有直接抑制突变的KRAS、靶向KRAS下游信号通路中的各种效应因子、抑制KRAS突变协同致死基因等。本文对近年来靶向KRAS基因突变肿瘤的药物治疗研究进展作一简要综述。

直接抑制突变的KRAS

KRAS G12C抑制剂对于直接的KRAS抑制剂,最初的研究尝试通过竞争性抑制GTP与KRAS结合来抑制KRAS活性,但相较于GDP,GTP在细胞内浓度更高,GTP与KRAS的结合能力更强,且KRAS蛋白的结构相对平滑,缺少能够与小分子抑制剂结合的深“口袋”,使得直接抑制KRAS基因在临床上有困难。近年来,随着新结合位点的发现及抑制剂的优化,直接的KRAS抑制剂得到发展。Ostrem等[4]发现了KRAS G12C的不可逆变构抑制剂,该化合物直接与KRAS上的变构口袋S-ⅡP(switch-Ⅱ pocket)结合,逆转KRAS G12C对GDP和GTP的亲和性,使得KRAS G12C更易与GDP结合,促使KRAS失活。Lim等[5]报道了另一种KRAS G12C抑制剂SML-10-70-1,它是一种具有细胞渗透性的前药,能够在不影响正常KRAS的情况下,与KRAS基因的鸟苷酸结合位点结合,使KRAS基因处于失活状态。等位基因特异性靶向化合物ARS-853是一种新型强效抑制剂,能够特异性靶向KRAS-G12C的结合口袋及交换口袋,与GEFs竞争结合KRAS G12C-GDP,使KRAS G12C一直处于与GDP结合状态,显著减少KRAS-GTP,抑制KRAS与下游信号分子的相互作用[6-7]。虽然这些化合物能够在体外抑制突变的KRAS肿瘤,但其在体内能否发挥作用仍然未知。Janes等[8]的研究表明,化合物ARS-1620在体内也可靶向抑制KRAS G12C,且具有高效能和高选择性,表现出新一代KRAS G12C特异性抑制剂的治疗潜力。进一步研究显示,KRAS直接抑制剂的效能可能受内源性耐药的影响[9],与其他药物联合应用可提高其效能。ARS-1620的耐药机制包括有丝分裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)通路的激活及诱导PI3K-AKT通路失活的功能丧失,故在ARS-1620耐药的体内和体外模型中,联用ARS1620与PI3K抑制剂可有效预防耐药[10]

AMG510是首个进入临床试验(NCT03600883)的KRAS G12C口服抑制剂,其与KRAS-GDP结合的效能为ARS 1620的10倍。Canon等[11]的体外研究表明,AMG510可缩小KRAS G12C突变肿瘤的体积。该药物的Ⅰ期临床研究[12]招募了接受≥2线治疗的KRAS G12C突变晚期实体瘤患者35例,在10例可评估的NSCLC患者中,5例患者肿瘤缩小(PR),4例患者病情停止进展(SD),表明AMG510在NSCLC患者中的客观缓解率(objective response rate, ORR)达50%,疾病控制率(disease control rate, DCR)达90%。入组NSCLS患者扩增至23人后ORR为48%,DCR达96%,与治疗相关的不良事件发生率为35.3%,表明人数增加后AMG510仍然表现出与之前一致的安全性、耐受性和疗效[13]。也有学者报道多例患者接受AMG 510治疗超过6个月且疗效稳定[14]。该药物的治疗缓解持续时间仍值得继续研究。目前Ⅰ期试验着眼于AMG 510单一疗法,对于肿瘤产生治疗耐药的问题,还需要更多联合疗法的临床研究。

口服小分子抑制剂MRTX849的临床前研究显示,在KRAS G12C阳性细胞系和患者来源的异种移植模型中,应用MRTX849使肿瘤明显消退[15]。其Ⅰ期临床研究同样取得了令人欣喜的结果[16],在NSCLC患者中ORR为50%,DCR达100%。KRAS G12C抑制剂JNJ-74699157/ARS3248已进入临床研究阶段。

泛KRAS抑制剂  除KRAS-G12C外,其他KRAS突变亚型如KRAS-G12D、KRAS-G12V等在肿瘤的发展中也起重要作用。

RAS-GDP与RAS-GTP的转换需要GEFs的参与,如SOS(son of sevenless)蛋白等。特异性SOS1抑制剂可与SOS1蛋白结合来抑制所有KRAS突变亚型的活性,属于泛KRAS抑制剂。Leshchiner等[17]发现,SAH-SOS1(stabilized alpha helices of son of sevenless 1)肽是具有高亲和性的KRAS结合配体,可以靶向作用于KRAS上的SOS1结合口袋,破坏SOS1与KRAS的相互作用,在野生型和多种KRAS突变类型中均起作用。Hillig等[18]研究证明,小分子抑制剂BAY-293能有效下调肿瘤细胞中的活性RAS,在具有野生型KRAS的细胞中,可完全抑制RAS-RAF-MEK-ERK通路。另一种泛KRAS抑制剂BI1701963,在临床前研究中与MEK抑制剂联用,能够显著影响KRAS信号传导,并通过互补作用机制提高抗肿瘤活性[19]。其单药应用及与MEK抑制剂曲美替尼联合应用已进入临床研究,有望进一步提高疗效。

KRAS蛋白的激活还需要效应因子的参与,Welsch等[20]发现了一种小分子配体,能够与KRAS结合,破坏KRAS蛋白与其效应因子的相互作用,从而抑制突变的KRAS基因,这种小分子配体有待进一步研究。

对外泌体进行修饰,可能为KRAS突变胰腺癌的治疗带来新的思路。外泌体为细胞分泌的细胞外囊泡,其可递送RNA干扰(RNA interference, RNAi),在体内迁移并进入癌细胞。用经过基因修饰的外泌体作为载体,针对KRAS G12D突变体的小干扰RNA(siRNA)或短发夹RNA(shRNA)进行包裹与递送,使其在体内靶向KRAS G12D,可有效抑制肿瘤细胞生长[21]

改变膜定位  KRAS作为一种分子开关,定位于细胞膜,调节细胞内下游信号网络。KRAS的膜定位由多种酶调节,如法尼基转移酶(farnesyltransferase)、香叶基转移酶、RAS转换酶1(RAS converting enzyme 1,RCE1)、异戊烯半胱氨酸羧基甲基转移酶抗体(isoprenylcystein carboxyl methyltransferase,ICMT)等。与KRAS蛋白相比,法尼基转移酶更适合成为药物靶点。在法尼基蛋白转移酶抑制剂(farnesyltransferase inhibitor, FTI)中,一代的Tipifarnib(R115777)和二代的Salirasib虽然在体内与体外模型中均可抑制法尼基转移酶的活性[22],但在Ⅱ期临床实验中未能表现出临床效应。进一步研究发现,这种无效性可能是由于KRAS蛋白被香叶基转移酶选择性修饰,出现KRAS基因扩增或脱靶效应[23]。已在小鼠模型中证明CAAX加工酶RCE1和ICMT的抑制剂有效,但仍需进一步研究。两种法尼基化结合伴侣,即磷酸二酯酶-6δ(phosphodiesterase-6δ, PDE6δ)和半乳糖凝集素-3,被发现参与KRAS法尼基化过程,已成为KRAS基因突变治疗的新靶点。PDE6δ抑制剂,即苯并咪唑衍生物Deltarasin1,可破坏KRAS与PDE6δ的相互作用,使得KRAS无法定位于细胞膜[24]。第二代的PDE6δ抑制剂具有更低的毒性和更高的选择性,能够更有效地抑制KRAS突变肿瘤[25]。但PDE6δ会与多少种法尼基化蛋白相互作用目前并不明确,这可能会使PDE6δ抑制剂对目标KRAS蛋白缺乏足够的选择性。

靶向KRAS效应信号通路

抑制RAF-MEK-ERK  BRAF是一种丝氨酸/苏氨酸激酶,是MAPK途径中的第1个激酶,被与GTP结合的KRAS基因募集到质膜并激活后,活化下游效应因子。BRAF抑制剂达拉非尼(Dabrafenib)和危罗非尼(Vemurafenib)已被批准用于BARF突变的转移性黑色素瘤的治疗[26]。有证据表明单用达拉非尼对BARFV600突变型NSCLC有效[27],但单用RAF激酶抑制剂在KRAS突变的细胞系中表现不佳[28]。因为根据MAPK悖论(反向激活),抑制BRAF会诱导ERK磷酸化,导致KRAS突变患者耐药[29-30]。Sanclemente等[31]研究发现,CRAF在KRAS突变的肺癌中起关键作用,在KRAS/Trp53突变的晚期肺腺癌中,消融CRAF使肿瘤消退,且不会抑制MAPK通路,能够减少毒性,而消融BRAF则无明显作用,说明CRAF是具有潜力的治疗靶点。

MEK是KRAS和BRAF的下游信号,是MAPK信号级联的下游效应因子。活化的RAF将磷酸化双特异性激酶MEK1和MEK2的丝氨酸/苏氨酸残基,激活MEK,进而激活丝氨酸/苏氨酸激酶ERK,从而激活转录因子,促进细胞增殖。由于BARF抑制剂未能达到良好的临床效果,故靶向MEK成为新的治疗选择。MEK1/MEK2抑制剂司美替尼(Selumetinib, AZD6244)和曲美替尼(Trametinib, GSK1120212)正处于KRAS突变的NSCLC的治疗研究中。临床前期研究和动物实验表明司美替尼可抑制BRAFKRAS突变的肿瘤生长。司美替尼/多西紫杉醇Ⅱ期研究亚组分析表明,KRAS G12C和G12V突变的肿瘤可能对司美替尼更敏感[32]。2017年报道的针对KRAS突变NSCLC患者的随机Ⅲ期临床试验显示,司美替尼和多西紫杉醇联用与多西紫杉醇单一疗法相比,联用组在ORR方面有优势,但未改善无进展生存期(progression free survival,PFS)(3.9个月vs.2.8个月, P=0.44)和总生存期(overall survival,OS)(8.7个月vs.7.9个月, P=0.64)[33]。也有试验显示,司美替尼与厄洛替尼(Erlotinib)联用治疗KRAS突变型或野生型NSCLC,与厄洛替尼单用相比,预后无明显改善[34]

MEK抑制剂曲美替尼是一种口服的选择性MEK1/MEK2抑制剂,能够有效抑制MEK1和MEK2,从而抑制ERK1/2磷酸化,起到抑制肿瘤生长的作用。在针对KRAS突变NSCLC的Ⅱ期临床试验(NCT01362296)中,曲美替尼和多西紫杉醇组的ORR与PFS结果相似(ORR:12% vs.12%, P=1.00;PFS:12周vs.11周, P=0.52)[35]。在NSCLC患者中进行的Ⅰb期临床试验结果,曲美替尼联合培美曲塞的总ORR达14%,而在KRAS突变的NSCLC患者中达17%;曲美替尼联合多西紫杉醇的总ORR达21%,KRAS突变的NSCLC患者中达24%,曲美替尼联合用药的ORR较之前的研究更高[36-37],但仍需要进一步研究确认结果。MEK抑制剂同样存在耐药的问题。非受体蛋白酪氨酸激酶2 (Src homology phosphortyrosyl phosphatase 2,SHP2)编码PTEN 11,对KRAS突变肿瘤在体内的生长有一定作用[38]。SHP2可能成为KRAS突变肿瘤的关键性治疗靶点。SHP2抑制剂SHP099与MEK抑制剂联用能有效抵抗MEK抑制剂耐药[39]。Ruess等[40]发现,SHP2对于MEK抑制剂的耐药形成具有关键作用,SHP2与MEK抑制剂合用靶向KRAS突变肿瘤具有协同效果,使PDAC与NSCLC的小鼠源性和人源性移植物模型中肿瘤的生长得到了控制。最新研究证明,KRAS二聚化能够调节野生型KRAS对KRAS突变肿瘤细胞的抑制效果,同时也是KRAS突变肿瘤细胞对MEK抑制剂耐药的基础。当KRASD154Q替换野生型KRAS时,这些效应均消失,KRASD154Q是一种破坏a4-a5KRAS二聚化的突变体,在体外和体内均未改变KRAS的其他基本生化特性,说明二聚化在KRAS突变细胞的致癌活性中具有关键作用[41]。蛋白磷酸酯酶2A(protein phosphatase 2A, PP2A)被抑制也是KRAS突变细胞对MEK抑制剂耐药的机制之一[42]

KRAS突变肿瘤对RAF抑制剂的耐药通常由ERK的反馈激活引起,联用RAF抑制剂与ERK抑制剂被认为是一种预防耐药的有效策略。一项近年的临床前研究表明,在KRAS突变的肺癌和胰腺癌小鼠模型中,联合使用MEK抑制剂与ERK抑制剂GDC-0994能有效抑制肿瘤生长[43]

抑制PI3K-AKT-mTOR  PIK3信号通路通常能独立于RAF-MEK-ERK信号通路而促进肿瘤细胞生长。依赖于RAF-MEK-ERK信号存活的KRAS突变型肿瘤,被称为KRAS突变依赖型肿瘤,而部分肿瘤细胞可以通过其他信号通路继续生存,为KRAS突变非依赖型肿瘤[44]。对于KRAS突变非依赖型肿瘤,共抑制MEK和PIK3能够产生显著的协同效果[45]。新型PIK3抑制剂(如BKM120、GDC0941和XL147)在PIK3 CA突变的晚期NSCLC患者中进行Ⅱ期临床试验(NCT01297491、NCT01493843)的结果显示,单独使用PIK3抑制剂治疗KRAS突变肿瘤的效果不佳[46]

mTOR是一种丝氨酸/苏氨酸激酶,也是PIK3家族的成员。一项Ⅱ期临床试验显示,与安慰剂组相比,使用mTOR抑制剂地磷莫司(Ridaforolimus)治疗NSCLC患者,PFS可显著改善(18个月 vs.5个月, P=0.009),但缓解率(remission rate,RR)仅为1%,并且OS无显著差异[47],仍需要更大型的Ⅲ期临床试验以进一步验证其在改善PFS、OS上的作用。研究发现,2-氨基-4-甲基喹唑衍生物xh002作为PI3K/mTOR双抑制剂,在突变的NSCLC中具有抗肿瘤效果[48]

基于之前的研究,研究人员考虑同时抑制PI3K/AKT/mTOR和BRAF/MEK/ERK两条通路可能是更可行的策略。实验证明,这是完全阻断KRAS信号传导的一种有效方法[49]。目前,PI3K联合MEK或mTOR抑制剂用于晚期实体肿瘤的Ⅰ期试验尚在进行[50-51]。一项Ⅰ期临床试验的结果显示,在同时接受司美替尼和AKT抑制剂MK-2206联合治疗的患者中,23%的NSCLC患者得到了有效的治疗,表明双药联合具有增效作用[52]。此外,mTOR抑制剂Panobinostat与吉非替尼联用,靶向作用于TAZ(tafazzin),可有效防止KRAS突变肿瘤对吉非替尼产生耐药[53]

抑制JAK-STAT3信号通路  在KRAS基因突变的结肠癌和NSCLC中,抑制MEK将反馈激活信号传导与转录激活因子3(signal transducer and activator of transcription 3, STAT3),从而产生耐药,因此用JAK抑制剂Ruxolitinib抑制JAK活性,降低STAT3的磷酸化水平,能提高肿瘤对MEK抑制剂的敏感性[54]。在KRAS突变的胰腺癌患者中,同时抑制MEK-ERK和STAT3,往往能表现出更好的疗效[55]。最新的Ⅱ期研究结果显示,Ruxolitinib(15 mg,bid)与Pemetrexed/顺铂联合使用,可作为Ⅲb/Ⅳ期或复发型非鳞状NSCLC的一线治疗方案[56]

抑制热休克蛋白  热休克蛋白90(heat shock protein 90, HSP90)是一种保守且有高度活性的蛋白,作为分子伴侣,可稳定肿瘤发病通路中重要信号转导因子的蛋白构象以及保护蛋白酶体不被降解。在肿瘤细胞中HSP90活性高于正常细胞,这使得HSP90成为有前景的抗肿瘤药物靶点。小鼠肿瘤模型数据显示, 抑制HSP90的活性可以对NSCLC起到治疗效果[57]。然而,在临床试验中单独使用HSP90抑制剂Ganetespib或与其他药物(如化疗药物、MEK抑制剂、PIK3/mTOR抑制剂)联用治疗KRAS突变肿瘤的疗效均不理想[58]。第二代抑制剂Ganetespib在治疗KRAS突变的NSCLC时,会反馈激活ERK-p90RSK-mTOR信号,故同时靶向抑制HSP90和p90RSK可能成为治疗KRAS突变肿瘤的新方法[59]。AUY922是一种高效的、ATP竞争性的HSP90抑制剂,体内外实验均证明其能抑制肿瘤生长,最新的Ⅱ期临床试验结果表明,AUY922在NSCLC患者中是有效的[60]。HSP90与mTOR抑制剂的组合应用可能具有协同效果,需在临床试验中进一步探索[61]。同样,加入HSP90抑制剂NVP-AUY922(Luminespib)后,可增加KRAS突变的NSCLC细胞对曲美替尼的敏感性[62]

作用于合成致死位点  KRAS突变使癌细胞的生长依赖于其他协同基因的共同作用,抑制这些协同致死基因是杀伤肿瘤细胞的有效方法。Kumar等[63]发现GATA结合蛋白2(GATA binding protein 2,GATA-2)是KRAS突变的关键基因蛋白。Costa-Cabral等[64]发现细胞周期蛋白依赖性激酶1(cyclin dependent kinase 1, CDK1)是KRAS突变肿瘤细胞的协同致死基因蛋白,利用CDK抑制剂AZD5483处理KRAS突变的肿瘤细胞,可将细胞阻滞于G0/G1期。同样,CDK4也具有协同致死作用。在KRAS突变的NSCLC的临床前模型中,CDK4/6抑制剂Palbociclib与曲美替尼联用具有一定的疗效[65]。一项Ⅱ期临床试验(NCT01833143)发现,将NF-κB的蛋白酶体抑制剂硼替佐米(Bortezomib)用于KRAS G12D突变的、无吸烟史的晚期NSCLC患者后,中位生存期达到13个月[66]

其他机制的KRAS药物  MET是一个跨膜酪氨酸激酶受体,参与激活KRAS信号通路,可激活RAS/PI3K/AKT/mTOR通路,使表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI)产生获得性耐药。目前的抑制剂包括靶向MET受体的单克隆抗体Onartuzumab及小分子c-Met受体酪氨酸激酶抑制剂Tivantinib(ARQ 197)。一项在晚期NSCLC患者中进行的Ⅱ期临床试验显示,厄洛替尼与Tivantinib联用与厄洛替尼单药相比,PFS有明显改善(P < 0.01)[67]。另一项Ⅱ期临床研究中,Onartuzumab联合厄洛替尼治疗MET阳性的NSCLC,患者预后较好[68]

局部黏着斑激酶参与细胞迁移的RHOA-FAK途径,在一些KRAS突变的肿瘤中发挥重要作用。一项Ⅱ期临床研究评估在KRAS突变的NSCLC患者中应用一种FAK抑制剂Defactinib(V2-6063)的疗效,结果显示12周的PFS为36%,因此认为该抑制剂具有一定的临床应用前景[69]

免疫治疗具有良好的应用前景。24%~55%的KRAS突变型肺腺癌的肿瘤细胞表达PD-L1,KRAS/TP53共突变肿瘤高表达PD-L1,而KRAS/STK11共突变的肺腺癌低表达PD-L1,易产生原发耐药[70]。研究发现,PD-1阻断免疫治疗法对TP53/KRAS双突变的患者有更好的治疗效果[71]KRAS突变与TP53突变被提出作为生物标志物来预测阻断PD-1/PD-L1的临床效果。进一步研究显示,免疫治疗对KRAS/LKB1突变的患者无效,与募集中性粒细胞和阻断T细胞的炎性细胞因子显著增加有关[72]。PD-L1抑制剂与细胞毒T淋巴细胞相关抗原4(cytotoxic T lymphocyte-associated antigen-2, CTLA-4)抑制剂合用能够在NSCLC中起效[73]

KRAS突变肿瘤细胞的代谢通路常常被重新编码,使其能为肿瘤生长提供大量能量,故靶向KRAS突变介导的代谢功能也是治疗KRAS突变肿瘤的策略之一。在PDAC中,KRAS突变能通过增加自噬的方式,由溶酶体介导产生细胞降解产物以维持代谢。既往研究证实,KRAS主要通过RAF-MEK-ERK通路调控糖代谢。Bryant等[74]发现,ERK抑制剂能够抑制糖酵解和线粒体活性,这使得肿瘤细胞更依赖自噬过程,利用这种依赖性,同时使用RAF-MEK-ERK通路抑制剂和自噬抑制剂羟化氯喹(hydroxychloroquine),能够增强肿瘤细胞对羟化氯喹的反应性,由此推测合用多种代谢通路抑制剂可以提高疗效。

近年来,多种与KRAS突变通路相关的激酶被发现,可能成为有潜力的治疗靶点。KRAS突变依赖性肿瘤在体内和体外的生长与生存需要糖原合成酶激酶3(glycogen synthase kinase 3, GSK3)的参与,而KRAS突变非依赖性肿瘤则不然。抑制GSK3的底物,能抑制c-Myc上的T-58和β-catenin上的S33/S37/T41位点的磷酸化,从而上调c-Myc与β-catenin的水平,而c-Myc与β-catenin能够增强GSK3抑制剂SB-732881-H (SB)的抗肿瘤活性,进而抑制肿瘤生长。更有临床意义的是,GSK3抑制剂SB能够抑制G12D、G12V和G12C型KRAS突变的人源肿瘤异种移植模型在体内的生长,移植物来源于对化疗、放疗均不敏感的胰腺癌患者,这给KRAS依赖性肿瘤的治疗提供了新思路[75]。极光激酶A(aurora kinase A, AURKA),是一种丝氨酸/苏氨酸激酶,常在KRAS突变的消化道恶性肿瘤中过表达,在磷酸化核糖体蛋白S6激酶(ribosomal protein S6 kinase B1, RPS6KB1)上起关键作用,应用AURKA抑制剂Alisertib能够抑制RPS6KB1活化,从而抑制KRAS突变的胃肠道肿瘤细胞的增殖,这为KRAS突变的消化道肿瘤提供了可行的治疗方案[76]。在PDAC中,1α-磷脂酰肌醇-4-磷酸-5-激酶(phosphatidylinositol 4-phosphate 5-kinase type-1α, PIP5K1A)直接与KRAS的特定区域结合,通过为PI3K提供PIP2促进KRAS信号通路激活,消除PIP5K1A能够抑制肿瘤增殖,并能提高胰腺肿瘤细胞系对MAPK抑制剂的敏感性,说明抑制PIP5K1A可能成为抑制KRAS的有效策略[77]。在肺腺癌中,KRAS信号的通路激活需要解整合素金属蛋白酶17(metallopeptidase domain 17,ADAM17),ADAM17激活IL-6R,进一步激活ERK1/2MAPK通路,故靶向抑制ADAM17-sIL-6R轴,在人源性移植物中可抑制肿瘤生长,是治疗肺腺癌的新策略[78]

药物联用  目前已有KRAS G12C靶向抑制剂(如AMG510、MRTX849等)进入临床研究,取得了一定的疗效,但在体外试验和临床试验中均存在耐药。目前已有针对耐药问题展开药物联用的体外实验及临床研究。在AMG510的临床前研究中,AMG510单药与帕博利珠单抗(Pembrolizumab)单药均只能使1只(1/10)小鼠肿瘤完全消退,而两药联用增强了抗肿瘤效果,10只小鼠中有9只可达到肿瘤完全消退,且持续112天以上[11]。可能的机制为:AMG510能够激发肿瘤微环境中的促炎症反应,增强T细胞的活化及对肿瘤抗原的识别能力,促进长期抗肿瘤T细胞反应。AMG510在与SHP2抑制剂、MEK抑制剂及化疗药物联用时均能表现出协同作用。在MRTX849的临床前研究中,MRTX849与靶向RTK、mTOR或细胞周期的药物联用也表现出增强效应[15]

对于其他KRAS突变亚型,虽已广泛开展KRAS抑制剂及靶向KRAS下游信号通路药物的临床研究,但单药应用效果不佳,仍需探究药物联用的疗效。在曲美替尼与多西紫杉醇联用的Ⅱ期临床研究中,总ORR达33%,中位PFS为4.1个月,中位OS为11.1个月,较单药(ORR:12%)疗效提高[79]。亚组分析显示非G12C突变患者的整体疗效比G12C突变患者好,ORR(37% vs. 26%)、PFS(4.1个月 vs.3.3个月)及OS(16.3个月 vs. 8.8个月)均显示出一定的优势,虽然差异无统计学意义,但也为非G12C突变患者带来了希望。

结语  相较于先前大部分靶向KRAS的药物在进入临床研究后的不佳表现,直接靶向KRAS的抑制剂如特异性KRAS G12C抑制剂在临床研究中取得了令人惊喜的效果。但KRAS G12C抑制剂在不同肿瘤中疗效不一,且疗效持续时间未知,治疗中潜在的获得性耐药也是需要考虑的问题。多种不同机制靶向KRAS的药物联合用药,治疗药物联用,均已在临床前研究中表现出协同作用,联合用药已成为提高药物疗效、解决耐药问题的必然趋势。

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文章信息

卞赟艺, 杨晓冬, 詹成, 姚光宇, 毕国澍, 范虹
BIAN Yun-yi, YANG Xiao-dong, ZHAN Cheng, YAO Guang-yu, BI Guo-shu, FAN Hong
KRAS基因突变及靶向药物的研究进展
Progress in pharmacological strategies targeting KRAS gene mutated cancers
复旦学报医学版, 2020, 47(3): 439-447, 455.
Fudan University Journal of Medical Sciences, 2020, 47(3): 439-447, 455.
Corresponding author
FAN Hong, E-mail:fan.hong@zs-hospital.sh.cn.
基金项目
国家自然科学基金(81672268);上海市自然科学基金(17ZR1405200)
Foundation item
This work was supported by the National Natural Science Foundation of China (81672268) and Natural Science Foundation of Shanghai, China (17ZR1405200)

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