NTRK1 rearrangement in colorectal cancer patients: evidence for actionable target using patient-derived tumor cell line.
NTRK1 rearrangement in colorectal cancer patients: evidence for actionable target using patient-derived tumor cell line.
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DOI：
10.18632/oncotarget.5494
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发表时间：
2015-11-17
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影响因子：
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通讯作者：
Lee J
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作者：
Lee SJ;Li GG;Kim ST;Hong ME;Jang J;Yoon N;Ahn SM;Murphy D;Christiansen J;Wei G;Hornby Z;Lee DW;Park JO;Park YS;Lim HY;Hong SN;Kim SH;Kang WK;Park K;Park WY;Kim KM;Lee J
我们研究了转移性胃肠道癌患者NTRK 1重排的发生率，并证明了这些患者对靶向治疗的临床反应潜力。我们前瞻性地收集了一年的肿瘤组织标本，同时产生了患者源性肿瘤细胞（PDCs）。最初使用TrkA免疫组织化学（IHC）筛选样本的TrkA蛋白表达。在TrkA IHC阳性结果的情况下，通过荧光原位杂交（FISH）和下一代测序（NGS）进一步检查样本，以确认NTRK 1重排的存在。2014年1月至2014年12月，共有74例转移性结直肠癌（CRC）患者和66例胃癌（GC）患者接受了TrkA IHC的初步筛查。74例CRC患者中的2例（2.7%）和66例GC患者中的1例（1.5%）通过IHC检测为TrkA表达阳性。所有三个IHC阳性病例都有FISH检测NTRK 1重排的证据。对3例IHC阳性病例进行了NGS，并在2例CRC病例中证实了TPM 3-NTRK 1重排。1例经IHC检测TrkA表达的GC患者未发生NTRK 1重排。从NTRK 1阳性的CRC患者建立的PDC对NTRK 1重排呈阳性。恩曲替尼是一种泛TRK抑制剂，可显著抑制NTRK 1重排PDCs的细胞增殖，这种抑制作用与TrkA失活和下游信号通路下调有关。TrkA IHC是临床上检测NTRK 1重排的一种有效的初始筛查方法。抑制TrkA激酶是一种有前途的靶向治疗癌症患者的肿瘤窝藏NTRK 1重排。
We have investigated the incidence of NTRK1 rearrangements in metastatic gastrointestinal cancer patients and demonstrated the potential for clinical response of these patients to targeted therapy. We prospectively collected tumor tissue specimens for one year and simultaneously generated patient-derived tumor cells (PDCs). Specimens were initially screened for TrkA protein expression using TrkA immunohistochemistry (IHC). In the case of TrkA IHC positive results, samples were further examined by fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) to confirm the presence of NTRK1 rearrangements. From January 2014 to December 2014, a total of 74 metastatic colorectal cancer (CRC) patients and 66 gastric cancer (GC) patients were initially screened by TrkA IHC. Two of the 74 CRC patients (2.7%) and one of the 66 GC patients (1.5%) were positive for TrkA expression by IHC. All three IHC positive cases had evidence of NTRK1 rearrangements by FISH. NGS was performed on the 3 IHC positive cases and confirmed TPM3-NTRK1 rearrangements in the two CRC cases. One GC patient with TrkA expression by IHC did not harbor an NTRK1 rearrangement. PDCs established from the NTRK1 positive CRC patients were positive for the NTRK1 rearrangement. Entrectinib, a pan-TRK inhibitor, profoundly inhibited cell proliferation of NTRK1-rearranged PDCs with such inhibition associated with inactivation of TrkA, and down-regulation of downstream signaling pathways. TrkA IHC is an effective, initial screening method for NTRK1 rearrangement detection in the clinic. Inhibition of the TrkA kinase is a promising targeted therapy for cancer patients whose tumors harbor a NTRK1 rearrangement.