Department of Pediatrics and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, and the Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2021 Sep 15;27(18):4974-4982. doi: 10.1158/1078-0432.CCR-21-0465. Epub 2021 Apr 23.
Chromosomal rearrangements of resulting in gene fusions ( gene fusions) have been clinically validated as oncogenic drivers in a wide range of human cancers. Typically, gene fusions involve both inter- and intrachromosomal fusions of the 5' regions of a variety of genes with the 3' regions of genes leading to TRK fusion proteins with constitutive, ligand-independent activation of the intrinsic tyrosine kinase. The incidence of gene fusions can range from the majority of cases in certain rare cancers to lower rates in a wide range of more common cancers. Two small-molecule TRK inhibitors have recently received regulatory approval for the treatment of patients with solid tumors harboring gene fusions, including the selective TRK inhibitor larotrectinib and the TRK/ROS1/ALK multikinase inhibitor entrectinib. In this review, we consider the practicalities of detecting tumors harboring gene fusions, the pharmacologic properties of TRK inhibitors currently in clinical development, the clinical evidence for larotrectinib and entrectinib efficacy, and possible resistance mechanisms.
导致基因融合（gene fusions）的染色体重排已在广泛的人类癌症中被临床验证为致癌驱动因素。通常，基因融合涉及多种基因的 5'区域与 基因的 3'区域之间的相互和染色体内融合，导致 TRK 融合蛋白具有组成型、配体非依赖性的内在酪氨酸激酶激活。基因融合的发生率从某些罕见癌症中的大多数病例到更常见的广泛癌症中的较低比率不等。最近，两种小分子 TRK 抑制剂已获得监管部门批准，用于治疗携带基因融合的实体瘤患者，包括选择性 TRK 抑制剂 larotrectinib 和 TRK/ROS1/ALK 多激酶抑制剂 entrectinib。在这篇综述中，我们考虑了检测携带基因融合的肿瘤的实际情况、目前处于临床开发阶段的 TRK 抑制剂的药理特性、larotrectinib 和 entrectinib 疗效的临床证据以及可能的耐药机制。
