PMID- 26472021
OWN - NLM
STAT- MEDLINE
DCOM- 20161213
LR  - 20201116
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 6
IP  - 36
DP  - 2015 Nov 17
TI  - NTRK1 rearrangement in colorectal cancer patients: evidence for actionable target 
      using patient-derived tumor cell line.
PG  - 39028-35
LID - 10.18632/oncotarget.5494 [doi]
AB  - BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
FAU - Lee, Su Jin
AU  - Lee SJ
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Li, Gang Gary
AU  - Li GG
AD  - Ignyta Inc, San Diego, California, USA.
FAU - Kim, Seung Tae
AU  - Kim ST
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Hong, Min Eui
AU  - Hong ME
AD  - Department of Pathology and Translational Genomics, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Jang, Jiryeon
AU  - Jang J
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Yoon, Nara
AU  - Yoon N
AD  - Department of Pathology and Translational Genomics, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Ahn, Soo Min
AU  - Ahn SM
AD  - Department of Pathology and Translational Genomics, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Murphy, Danielle
AU  - Murphy D
AD  - Ignyta Inc, San Diego, California, USA.
FAU - Christiansen, Jason
AU  - Christiansen J
AD  - Ignyta Inc, San Diego, California, USA.
FAU - Wei, Ge
AU  - Wei G
AD  - Ignyta Inc, San Diego, California, USA.
FAU - Hornby, Zachary
AU  - Hornby Z
AD  - Ignyta Inc, San Diego, California, USA.
FAU - Lee, Dong Woo
AU  - Lee DW
AD  - Samsung Electrics, Seoul, Korea.
FAU - Park, Joon Oh
AU  - Park JO
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
AD  - The Innovative Cancer Medicine Institute, Samsung Medical Center, Sungkyunkwan 
      University School of Medicine, Seoul, Korea.
FAU - Park, Young Suk
AU  - Park YS
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Lim, Ho Yeong
AU  - Lim HY
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Hong, Sung No
AU  - Hong SN
AD  - Division of Gastroenterology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Kim, Seok-Hyeong
AU  - Kim SH
AD  - Department of Pathology and Translational Genomics, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Kang, Won Ki
AU  - Kang WK
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Park, Keunchil
AU  - Park K
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
FAU - Park, Woong Yang
AU  - Park WY
AD  - Samsung Genome Institute, Seoul, Korea.
FAU - Kim, Kyoung-Mee
AU  - Kim KM
AD  - Department of Pathology and Translational Genomics, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
AD  - The Innovative Cancer Medicine Institute, Samsung Medical Center, Sungkyunkwan 
      University School of Medicine, Seoul, Korea.
FAU - Lee, Jeeyun
AU  - Lee J
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul, Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Benzamides)
RN  - 0 (Indazoles)
RN  - 0 (NTRK1 protein, human)
RN  - EC 2.7.10.1 (Receptor, trkA)
RN  - L5ORF0AN1I (entrectinib)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Benzamides/pharmacology
MH  - Cell Line, Tumor
MH  - Colorectal Neoplasms/drug therapy/enzymology/*genetics/pathology
MH  - Female
MH  - Gene Rearrangement
MH  - Humans
MH  - Immunohistochemistry
MH  - Indazoles/pharmacology
MH  - Male
MH  - Middle Aged
MH  - Molecular Targeted Therapy
MH  - Prospective Studies
MH  - Receptor, trkA/antagonists & inhibitors/*genetics
MH  - Tumor Cells, Cultured
PMC - PMC4770754
OTO - NOTNLM
OT  - NTRK1 rearrangement
OT  - TRKA immunohistochemistry
OT  - colorectal cancer
COIS- CONFLICTS OF INTEREST No conflicts of interest.
EDAT- 2015/10/17 06:00
MHDA- 2016/12/15 06:00
PMCR- 2015/11/17
CRDT- 2015/10/17 06:00
PHST- 2015/06/22 00:00 [received]
PHST- 2015/09/30 00:00 [accepted]
PHST- 2015/10/17 06:00 [entrez]
PHST- 2015/10/17 06:00 [pubmed]
PHST- 2016/12/15 06:00 [medline]
PHST- 2015/11/17 00:00 [pmc-release]
AID - 5494 [pii]
AID - 10.18632/oncotarget.5494 [doi]
PST - ppublish
SO  - Oncotarget. 2015 Nov 17;6(36):39028-35. doi: 10.18632/oncotarget.5494.