NTRK1 rearrangement in colorectal cancer patients: evidence for actionable target using patient-derived tumor cell line
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Su Jin Lee1,*, Gang Gary Li2,*, Seung Tae Kim1,*, Min Eui Hong3, Jiryeon Jang1, Nara Yoon3, Soo Min Ahn3, Danielle Murphy2, Jason Christiansen2, Ge Wei2, Zachary Hornby2, Dong Woo Lee4, Joon Oh Park1,7, Young Suk Park1, Ho Yeong Lim1, Sung No Hong5, Seok-Hyeong Kim3, Won Ki Kang1, Keunchil Park1, Woong Yang Park6, Kyoung-Mee Kim3,7, Jeeyun Lee1
1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2Ignyta Inc, San Diego, California, USA
3Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
4Samsung Electrics, Seoul, Korea
5Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
6Samsung Genome Institute, Seoul, Korea
7The Innovative Cancer Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
*These authors have contributed equally to this work
Jeeyun Lee, e-mail: email@example.com
Kyoung-Mee Kim, e-mail: firstname.lastname@example.org
Keywords: colorectal cancer, NTRK1 rearrangement, TRKA immunohistochemistry
Received: June 22, 2015 Accepted: September 30, 2015 Published: October 12, 2015
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.
Conclusion: 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.
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