Yao Kun, Liu Hua, Yu Shui, Zhu Haohao, Pan Jie
Brain Science Basic Laboratory, The Affiliated Wuxi Mental Health Center with Nanjing Medical University, Wuxi, 214151, Jiangsu Province, China.
Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu Province, China.
Cancer Lett. 2022 May 1;533:215603. doi: 10.1016/j.canlet.2022.215603. Epub 2022 Feb 25.
Mutant isocitrate dehydrogenase 1/2 (mIDH1/2) is a promising target for the treatment of cancer. The FDA approved two molecular entities, ivosidenib and enasidenib, which target mIDH1 and mIDH2, respectively, for the treatment of relapsed/refractory acute myeloid leukemia (R/R AML). However, the alarming emergence of drug resistance to ivosidenib and enasidenib, a low response rate and relapse after short-term remission raised concerns about therapeutic options. Several mechanistic investigations of the resistance to these two drugs were performed, and multiple rational therapeutic strategies were proposed. The present review describes the primary and secondary resistance mechanisms of ivosidenib or enasidenib and the corresponding strategies for preventing drug resistance in detail. We discuss the opportunities and challenges for exploiting the next generation of mIDH1/2 inhibitors and translating the combination therapies presented in this paper into clinical applications for the treatment of the nonresponding or relapsed AML patients with IDH mutations.
突变型异柠檬酸脱氢酶1/2（mIDH1/2）是癌症治疗中一个很有前景的靶点。美国食品药品监督管理局（FDA）批准了两种分子实体药物，分别为艾伏尼布和恩杂鲁胺，它们分别靶向mIDH1和mIDH2，用于治疗复发/难治性急性髓系白血病（R/R AML）。然而，对艾伏尼布和恩杂鲁胺令人担忧的耐药性出现、低缓解率以及短期缓解后的复发引发了对治疗方案的关注。针对这两种药物的耐药性进行了多项机制研究，并提出了多种合理的治疗策略。本综述详细描述了艾伏尼布或恩杂鲁胺的原发性和继发性耐药机制以及相应的预防耐药性策略。我们讨论了开发下一代mIDH1/2抑制剂以及将本文介绍的联合疗法转化为临床应用以治疗无反应或复发的IDH突变型AML患者所面临的机遇和挑战。
