NTRK fusion-positive cancers and TRK inhibitor therapy.
NTRK fusion-positive cancers and TRK inhibitor therapy.
复制标题
DOI：
10.1038/s41571-018-0113-0
复制
发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
Drilon A
中科院分区：
文献类型：
--
作者：
Cocco E;Scaltriti M;Drilon A
涉及NTRK 1、NTRK 2或NTRK 3（分别编码神经营养因子受体TRKA、TRKB和TRKC）的NTRK基因融合体是各种成人和儿科肿瘤类型的致癌驱动因子。这些融合可以在临床上使用多种方法检测，包括肿瘤DNA和RNA测序以及血浆无细胞DNA分析。用第一代TRK抑制剂（如larotrectinib或entrectinib）治疗NTRK融合阳性癌症患者，无论肿瘤组织学如何，都具有高缓解率（>75%）。大多数患者对第一代TRK抑制剂耐受良好，毒性特征为偶尔的肿瘤外、靶向不良事件（归因于非恶性组织中的TRK抑制）。尽管许多患者的疾病得到了持久的控制，但晚期NTRK融合阳性癌症最终对TRK抑制难以治疗;耐药性可以通过获得NTRK激酶结构域突变来介导。幸运的是，第二代TRK抑制剂可以克服某些耐药突变，包括正在临床试验中探索的LOXO-195和TPX-0005。在这篇综述中，我们讨论了NTRK融合的生物学，在治疗初治和获得性耐药疾病环境中靶向这些驱动因素的策略，以及TRK抑制剂的独特安全性。
NTRK gene fusions involving either NTRK1, NTRK2, or NTRK3 (encoding the neurotrophin receptors TRKA, TRKB, and TRKC, respectively) are oncogenic drivers of various adult and paediatric tumour types. These fusions can be detected in the clinic using a variety of methods, including tumour DNA and RNA sequencing and plasma cell-free DNA profiling. 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 rates (>75%), regardless of tumour histology. First-generation TRK inhibitors are well tolerated by most patients, with toxicity profiles characterized by occasional off-tumour, on-target adverse events (attributable to TRK inhibition in non-malignant tissues). Despite durable disease control in many patients, advanced-stage NTRK fusion-positive cancers eventually become refractory to TRK inhibition; resistance can be 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. In this Review, we discuss the biology of NTRK fusions, strategies to target these drivers in the treatment-naive and acquired-resistance disease settings, and the unique safety profile of TRK inhibitors.
登录
查看更多内容
影响因子：
4.9
作者：
Ashraf S;Bouhana KS;Pheneger J;Andrews SW;Walsh DA
通讯作者：
Walsh DA
DOI：
10.1158/1078-0432.ccr-08-1815
发表时间：
2009-05-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Brodeur GM;Minturn JE;Ho R;Simpson AM;Iyer R;Varela CR;Light JE;Kolla V;Evans AE
通讯作者：
Evans AE
影响因子：
7.3
作者：
Amatu A;Sartore-Bianchi A;Siena S
通讯作者：
Siena S
DOI：
10.1002/neu.480251107
发表时间：
1994-11-01
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
BARBACID, M
通讯作者：
BARBACID, M
影响因子：
8
作者：
Arevalo, JC;Conde, B;Pérez, P
通讯作者：
Pérez, P