NTRK1 rearrangement in colorectal cancer patients: Evidence for actionable target using patient-derived tumor cell line

Su Jin Lee, Gang Gary Li, Seung Tae Kim, Min Eui Hong, Jiryeon Jang, Nara Yoon, Soo Min Ahn, Danielle Murphy, Jason Christiansen, Ge Wei, Zachary Hornby, Dong Woo Lee, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Sung No Hong, Seok Hyeong Kim, Won Ki Kang, Keunchil Park, Woong Yang ParkKyoung Mee Kim, Jeeyun Lee

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

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 downregulation of downstream signaling pathways.

Original languageEnglish
Pages (from-to)39028-39035
Number of pages8
JournalOncotarget
Volume6
Issue number36
DOIs
StatePublished - 2015

Keywords

  • Colorectal cancer
  • NTRK1 rearrangement
  • TRKA immunohistochemistry

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