PDF(Pubmed)
Abstract：
Fusions involving TRK protein tyrosine kinases are oncogenic drivers in a variety of tumors in children and adults, with a prevalence of ∼0.2% in non-small cell lung cancer. Diagnosis can be challenging due to structural features such as NTRK intron length, but next-generation sequencing (NGS), including RNA-based NGS, increases detection. The first-generation TRK inhibitors, larotrectinib and entrectinib, have demonstrated clinically meaningful antitumor activity in TRK fusion-positive cancers in a tumor-agnostic fashion and should be considered first-line therapeutic options for TRK fusion-positive lung cancers. Furthermore, the first-generation TRK inhibitors are well tolerated. Care should be taken, however, to monitor on-target adverse events, such as dizziness, weight gain, paresthesias, and withdrawal pain. On-target and off-target mechanisms mediating TRK inhibitor resistance may occur. Next-generation TRK inhibitors, such as selitrectinib, repotrectinib, and taletrectinib, are available on ongoing clinical trials and address on-target resistance. This review will focus on NTRK fusions and TRK-directed targeted therapy specifically in the context of lung cancer.
摘要：
涉及TRK蛋白酪氨酸激酶的融合是儿童和成人多种肿瘤的致癌驱动因素，非小细胞肺癌的患病率为0.2%。由于NTRK内含子长度等结构特征，诊断可能具有挑战性。但是下一代测序(NGS)，包括基于RNA的NGS，增加检测。第一代TRK抑制剂，拉罗列替尼和恩特列替尼，已经以肿瘤无关的方式在TRK融合阳性癌症中表现出临床意义的抗肿瘤活性，应被视为TRK融合阳性肺癌的一线治疗选择。此外，第一代TRK抑制剂耐受性良好.应该小心，然而,为了监测目标不良事件，如头晕，体重增加,感觉异常,和戒断疼痛。可能发生介导TRK抑制剂抗性的中靶和脱靶机制。下一代TRK抑制剂，比如selitrectinib,repotrectinib,和Taletrectinib,可用于正在进行的临床试验，并解决目标耐药问题。本文将重点介绍NTRK融合和TRK定向靶向治疗在肺癌中的应用。
