title: The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition.
abstract: 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.
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy. Electronic address: elena.ardini@nervianoms.com.
authors: Elena
authors: E
authors: Ardini
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Roberta
authors: R
authors: Bosotti
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Andrea Lombardi
authors: AL
authors: Borgia
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Cristina
authors: C
authors: De Ponti
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Alessio
authors: A
authors: Somaschini
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Rosaria
authors: R
authors: Cammarota
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Nadia
authors: N
authors: Amboldi
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Laura
authors: L
authors: Raddrizzani
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Andrea
authors: A
authors: Milani
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Paola
authors: P
authors: Magnaghi
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Dario
authors: D
authors: Ballinari
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Daniele
authors: D
authors: Casero
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Fabio
authors: F
authors: Gasparri
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Patrizia
authors: P
authors: Banfi
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Nilla
authors: N
authors: Avanzi
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Maria B
authors: MB
authors: Saccardo
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Rachele
authors: R
authors: Alzani
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Tiziano
authors: T
authors: Bandiera
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Eduard
authors: E
authors: Felder
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Daniele
authors: D
authors: Donati
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Enrico
authors: E
authors: Pesenti
authors: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy.
authors: Andrea
authors: A
authors: Sartore-Bianchi
authors: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy.
authors: Marcello
authors: M
authors: Gambacorta
authors: IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Marco A
authors: MA
authors: Pierotti
authors: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy.
authors: Salvatore
authors: S
authors: Siena
authors: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy.
authors: Silvio
authors: S
authors: Veronese
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Arturo
authors: A
authors: Galvani
authors: Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.
authors: Antonella
authors: A
authors: Isacchi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020917:Receptor, trkA / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014335:Tropomyosin / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; C498783:TPM3 protein, human; D014335:Tropomyosin; D020917:Receptor, trkA
keywords: Colorectal cancer; Kinase inhibitor; NMS-P626; TPM3-NTRK1 rearrangement; TRKA