复发难治性实体瘤NTRK靶向治疗新策略

A new strategy targeting NTRK in the treatment of recurrent and refractory solid tumors

NTRK融合基因是儿童和成人多种肿瘤类型的致癌基因。由这些融合基因编码的融合蛋白具有原肌球蛋白相关激酶(TRK)酪氨酸激酶结构域,为肿瘤靶向治疗提供了新的靶点。在不区分肿瘤组织类型的前提下,NTRK融合阳性患者使用第一代TRK抑制剂(如拉罗替尼或恩曲替尼)治疗后,其有效率高达75%。大多数患者对第一代TRK抑制剂耐受性良好,长期使用TRK抑制剂可出现继发性耐药,其耐药机制通过NTRK激酶结构域突变介导。部分耐药突变可由第二代TRK抑制剂克服,包括目前处于临床试验的LOXO-195和TPX-0005。NTRK靶向治疗具有良好的疗效及安全性,是NTRK融合复发难治性实体瘤治疗的新选择。

NTRK gene fusions are oncogenic drivers of various paediatric and adult tumor types.The fusion proteins encoded by these fusion genes have tropomyosin related kinase(TRK)tyrosine kinase domains,which provides novel targets for tumor targeted therapy.The treatment of patients with NTRK fusion-positive cancers with a first-generation TRK inhibitor,such as larotrectinib or entrectinib,is associated with high response rate(>75%),regardless of tumor histology.The first-generation TRK inhibitors are well tolerated by most patients.Chronic use of TRK inhibitors can lead to secondary resistance,and the resistance is mediated by the acquisition of NTRK kinase domain mutations.Fortunately,certain resistance mutations can be overcome by second-generation TRK inhibitors,including LOXO-195 and TPX-0005 that are being explored in clinical trials.As for its good efficacy and safety,NTRK targeted therapy is a new choice for the treatment of relapsed refractory solid tumors with NTRK fusion.