2. Academic Validation
  3. Tropomyosin receptor kinase: a novel target in screened neuroendocrine tumors

Tropomyosin receptor kinase: a novel target in screened neuroendocrine tumors

  • Endocr Relat Cancer. 2018 May;25(5):547-560. doi: 10.1530/ERC-17-0201.
Elke Tatjana Aristizabal Prada 1 2 3,  Vera Heinzle 1 2,  Thomas Knösel 1 4,  Svenja Nölting 1 2 3,  Gerald Spöttl 1 2 3,  Julian Maurer 1 2 3,  Christine Spitzweg 1 2 3,  Martin Angele 1 5,  Nina Schmidt 1 2 3,  Felix Beuschlein 3 6,  Günter K Stalla 7,  Rainer Blaser 8,  Klaus A Kuhn 8,  Christoph J Auernhammer 1 2 3
Affiliations

Affiliations

  • 1 Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Campus Grosshadern, Munich, Germany.
  • 2 Department of Internal Medicine 2, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany.
  • 3 Department of Internal Medicine 4, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany.
  • 4 Institute of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany.
  • 5 Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University-Hospital, Klinikum der Universität München, Ludwig-Maximilians-University of Munich, Munich, Germany.
  • 6 Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, Zurich, Switzerland.
  • 7 Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
  • 8 Institute of Medical Statistics and Epidemiology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
PMID: 29563190 DOI: 10.1530/ERC-17-0201
Abstract

Tropomyosin receptor kinase (Trk) inhibitors are investigated as a novel targeted therapy in various cancers. We investigated the in vitro effects of the pan-Trk inhibitor GNF-5837 in human neuroendocrine tumor (NET) cells. The human neuroendocrine pancreatic BON1, bronchopulmonary NCI-H727 and ileal GOT1 cell lines were treated with GNF-5837 alone and in combination with everolimus. Cell viability decreased in a time- and dose-dependent manner in GOT1 cells in response to GNF-5837 treatment, while treatment in BON1 and NCI-H727 cells showed no effect on cellular viability. Trk Receptor expression determined GNF-5837 sensitivity. GNF-5837 caused downregulation of PI3K-Akt-mTOR signaling, Ras-Raf-MEK-ERK signaling, the cell cycle and increased apoptotic cell death. The combinational treatment of GNF-5837 with everolimus showed a significant enhancement in inhibition of cell viability vs single substance treatments, due to a cooperative PI3K-Akt-mTOR and Ras-Raf-MEK-ERK pathway downregulation, as well as an enhanced cell cycle component downregulation. Immunohistochemical staining for Trk Receptors were performed using a tissue microarray containing 107 tumor samples of gastroenteropancreatic NETs. Immunohistochemical staining with TrkA receptor and pan-Trk receptor Antibodies revealed a positive staining in pancreatic NETs in 24.2% (8/33) and 33.3% (11/33), respectively. We demonstrated that the pan-Trk inhibitor GNF-5837 has promising anti-tumoral properties in human NET cell lines expressing the TrkA receptor. Immunohistochemical or molecular screening for Trk expression particularly in pancreatic NETs might serve as predictive marker for molecular targeted therapy with Trk inhibitors.

Keywords

Trk inhibitor; everolimus; neuroendocrine tumor; tropomyosin kinase receptor (Trk).

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