Oncogenic TRK fusions are amenable to inhibition in hematologic malignancies.
Oncogenic TRK fusions are amenable to inhibition in hematologic malignancies.
复制标题
致癌 TRK 融合可以抑制血液系统恶性肿瘤。
DOI：
10.1172/jci120787
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Diamond,E
中科院分区：
文献类型：
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作者：
Taylor,Justin;Pavlick,Dean;Yoshimi,Akihide;Marcelus,Christina;Chung,StephenS;Hechtman,JaclynF;Benayed,Ryma;Cocco,Emiliano;Durham,BenjaminH;Bitner,Lillian;Inoue,Daichi;Chung,YoungRock;Mullaney,Kerry;Watts,JustinM;Diamond,E
涉及神经营养受体激酶基因(NTRK1、NTRK2和NTRK3；以下简称TRK)的重排在成人和儿童的各种癌症中产生致癌融合。尽管TRK融合发生在所有实体肿瘤中不到1%，但抑制TRK会导致深刻的治疗反应，导致突破性治疗FDA批准TRK抑制剂larotrectinib用于成人和儿童实体肿瘤患者，无论组织学如何。与实体瘤相比，TRK融合的频率和靶向TRK在血液系统恶性肿瘤中的临床效果尚不清楚。在这里，通过对7,000多名血液恶性肿瘤患者的TRK融合进行评估，我们确定了在急性淋巴细胞白血病(ALL)、急性髓系白血病(AML)、组织细胞增生症、多发性骨髓瘤和树突状细胞肿瘤中存在TRK融合。虽然只有0.1%的患者发生了TRK融合(7,311例患者中有8例)，但在患者来源的异种移植和相应的ETV6-NTRK2融合的AML患者中，它们在体外和体内对TRK抑制具有反应性。这些数据表明，尽管TRK融合个别罕见，但总的来说，TRK融合存在于各种血液系统恶性肿瘤中，并预测了对TRK抑制的临床显著治疗反应。
Rearrangements involving the neurotrophic receptor kinase genes (NTRK1, NTRK2,andNTRK3; hereafter referred to as TRK) produce oncogenic fusions in a wide variety of cancers in adults and children. Although TRK fusions occur in fewer than 1% of all solid tumors, inhibition of TRK results in profound therapeutic responses, resulting in Breakthrough Therapy FDA approval of the TRK inhibitor larotrectinib for adult and pediatric patients with solid tumors, regardless of histology. In contrast to solid tumors, the frequency of TRK fusions and the clinical effects of targeting TRK in hematologic malignancies are unknown. Here, through an evaluation for TRK fusions across more than 7,000 patients with hematologic malignancies, we identified TRK fusions in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), histiocytosis, multiple myeloma, and dendritic cell neoplasms. Although TRK fusions occurred in only 0.1% of patients (8 of 7,311 patients), they conferred responsiveness to TRK inhibition in vitro and in vivo in a patient-derived xenograft and a corresponding AML patient withETV6-NTRK2fusion. These data identify that despite their individual rarity, collectively, TRK fusions are present in a wide variety of hematologic malignancies and predict clinically significant therapeutic responses to TRK inhibition.