The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition

被引：134

作者：

Ardini, Elena ^{[1
]}

Bosotti, Roberta ^{[1
]}

Borgia, Andrea Lombardi ^{[1
]}

De Ponti, Cristina ^{[1
]}

Somaschini, Alessio ^{[1
]}

Cammarota, Rosaria ^{[1
]}

Amboldi, Nadia ^{[1
]}

Raddrizzani, Laura ^{[1
]}

Milani, Andrea ^{[1
]}

Magnaghi, Paola ^{[1
]}

Ballinari, Dario ^{[1
]}

Casero, Daniele ^{[1
]}

Gasparri, Fabio ^{[1
]}

Banfi, Patrizia ^{[1
]}

Avanzi, Nilla ^{[1
]}

Saccardo, Maria B. ^{[1
]}

Alzani, Rachele ^{[1
]}

Bandiera, Tiziano ^{[1
]}

Felder, Eduard ^{[1
]}

Donati, Daniele ^{[1
]}

Pesenti, Enrico ^{[1
]}

Sartore-Bianchi, Andrea ^{[2
]}

Gambacorta, Marcello ^{[2
]}

Pierotti, Marco A. ^{[3
]}

Siena, Salvatore ^{[2
]}

Veronese, Silvio ^{[2
]}

Galvani, Arturo ^{[1
]}

Isacchi, Antonella ^{[1
]}

机构：

[1] Nerviano Med Sci Srl, Milan, Italy

[2] Osped Niguarda Ca Granda, Niguarda Canc Ctr, Milan, Italy

[3] IRCCS Ist Nazl Tumori, Milan, Italy

来源：

MOLECULAR ONCOLOGY | 2014年 / 8卷 / 08期

关键词：

TPM3-NTRK1; rearrangement; TRKA; Kinase inhibitor; NMS-P626; Colorectal cancer; NERVE GROWTH-FACTOR; ETV6-NTRK3 GENE FUSION; PAPILLARY THYROID CARCINOMAS; PROTEIN-TYROSINE KINASE; SIGNAL-TRANSDUCTION; TARGETED THERAPY; LUNG-CANCER; CELL-LINE; CONGENITAL INSENSITIVITY; PROTOONCOGENE PRODUCT;

D O I：

10.1016/j.molonc.2014.06.001

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The NTRK1 gene encodes Tropomyosin-related kinase A (TRKA), the high-affinity Nerve Growth Factor Receptor. NTRK1 was originally isolated from a colorectal carcinoma (CRC) sample as component of a somatic rearrangement (TPM3-NTRK1) resulting in expression of the oncogenic chimeric protein TPM3-TRKA, but there has been no subsequent report regarding the relevance of this oncogene in CRC. The KM12 human CRC cell line expresses the chimeric TPM3-TRKA protein and is hypersensitive to TRKA kinase inhibition. We report the detailed characterization of the TPM3-NTRK1 genomic rearrangement in KM12 cells and through a cellular screening approach, the identification of NMS-P626, a novel highly potent and selective TRKA inhibitor. NMS-P626 suppressed TPM3-TRKA phosphorylation and downstream signaling in KM12 cells and showed remarkable antitumor activity in mice bearing KM12 tumors. Finally, using quantitative reverse transcriptase PCR and immunohistochemistry (IHC) we identified the TPM3-NTRK1 rearrangement in a CRC clinical sample, therefore suggesting that this chromosomal translocation is indeed a low frequency recurring event in CRC and that such patients might benefit from therapy with TRKA kinase inhibitors. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

引用

页码：1495 / 1507

页数：13

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