协同增效策略在异柠檬酸脱氢酶1突变型肿瘤治疗中的研究进展  

Research Progress of Synergistic Enhancement Strategies in the Treatment of Tumors with Isocitrate Dehydrogenase 1 Mutation

作　　者：文菲 梁晴 查晓明 WEN Fei;LIANG Qing;ZHA Xiaoming(School of Engineering,China Pharmaceutical University,Nanjing 211198,China)

机构地区：[1]中国药科大学工学院,江苏南京211198

出　　处：《药学进展》2025年第4期267-280,共14页Progress in Pharmaceutical Sciences

基　　金：国家自然科学基金资助项目(No.81973187)。

摘　　要：代谢异常是肿瘤组织区别于正常组织的显著特征之一,针对肿瘤细胞代谢异常的特异性靶标进行干预,是肿瘤治疗的重要策略。异柠檬酸脱氢酶1(isocitrate dehydrogenase 1,IDH1)作为三羧酸循环中的关键限速酶,其主要功能是催化异柠檬酸转化为α-酮戊二酸(α-ketoglutaric acid,α-KG)。然而,突变型IDH1(mutant IDH1,mIDH1)却能将α-KG进一步转化为致癌代谢物—D-2-羟基戊二酸(D-2-hydroxyglutarate,D-2-HG),进而诱导肿瘤的发生与发展。目前,已有多种mIDH1抑制剂进入临床试验阶段,其中有3款已获批上市,但临床上也观察到了获得性耐药问题。m IDH1抑制剂的主要适应证为急性髓系白血病和脑胶质瘤,而对于其他携带有m IDH1的实体瘤,有效的抑制剂仍相对匮乏。近年来,协同治疗作为提高药物敏感性、减少不良反应、克服耐药性的有效手段,已广泛应用于肿瘤治疗领域。对IDH1相关癌症等疾病展开综述,重点聚焦于临床小分子抑制剂以及其与其他抗肿瘤药物联合进行协同治疗的研究进展,这将有助于加深对该领域的全面理解,并为进一步研发协同增效的抗肿瘤策略提供参考依据。Metabolic abnormality is one of the remarkable characteristics that distinguish tumor tissues from normal tissues.Intervening in the specific targets of abnormal metabolism in tumor cells is an important strategy for tumor treatment.The major function of isocitrate dehydrogenase 1(IDH1),a key rate-limiting enzyme in the tricarboxylic acid cycle,is to catalyze the conversion of isocitrate toα-ketoglutaric acid(α-KG).However,mutant IDH1(mIDH1)can further convertα-KG into D-2-hydroxyglutarate(D-2-HG),a carcinogenic metabolite,thus inducing the occurrence and development of tumors.Currently,quite a few mIDH1 inhibitors have entered the clinical trial stage,and three have been approved for marketing.However,the problem of acquired resistance has also been observed clinically.The main indications of mIDH1 inhibitors are acute myeloid leukemia and glioma.For other solid tumors carrying m IDH1 mutations,effective inhibitors are still relatively scarce.In recent years,as an effective means to improve drug sensitivity,reduce adverse reactions and overcome drug resistance,synergistic therapy has been widely applied for tumor treatment.This article reviews IDH1-related cancers and other diseases,focusing on the research progress of clinical small molecule inhibitors and their combination with other anti-tumor drugs for synergistic therapy,aiming to help deepen the comprehensive understanding of this field and provide some reference for further development of synergistic anti-tumor strategies.

关 键 词：肿瘤代谢 突变型异柠檬酸脱氢酶1抑制剂 协同治疗 

分 类 号：R730.58[医药卫生—肿瘤]