2. Academic Validation
  3. Novel preclinical gastroenteropancreatic neuroendocrine neoplasia models demonstrate the feasibility of mutation-based targeted therapy

Novel preclinical gastroenteropancreatic neuroendocrine neoplasia models demonstrate the feasibility of mutation-based targeted therapy

  • Cell Oncol (Dordr). 2022 Oct 21. doi: 10.1007/s13402-022-00727-z.
Fabrice Viol 1,  Bence Sipos 2,  Martina Fahl 3,  Till S Clauditz 4,  Tania Amin 3,  Malte Kriegs 5,  Maike Nieser 6,  Jakob R Izbicki 7,  Samuel Huber 3,  Ansgar W Lohse 3,  Jörg Schrader 8 9 10
Affiliations

Affiliations

  • 1 I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. f.viol@uke.de.
  • 2 Internal Medicine VIII, University Hospital Tübingen, Tübingen, Germany.
  • 3 I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
  • 4 Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 5 Laboratory of Radiobiology & Experimental Radiation Oncology, UCCH Kinomics Core Facility, Hubertus Wald Tumorzentrum, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 6 Center for Genomics and Transcriptomics, Tübingen, Germany.
  • 7 Department for General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 8 I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. jschrader@uke.de.
  • 9 Department for General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. jschrader@uke.de.
  • 10 Department of Medicine, Klinikum Nordfriesland, Husum, Germany. jschrader@uke.de.
PMID: 36269546 DOI: 10.1007/s13402-022-00727-z
Abstract

Purpose: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) form a rare and remarkably heterogeneous group of tumors. Therefore, establishing personalized therapies is eminently challenging. To achieve progress in preclinical drug development, there is an urgent need for relevant tumor models.

Methods: We successfully established three gastroenteropancreatic neuroendocrine tumor (GEP-NET) cell lines (NT-18P, NT-18LM, NT-36) and two gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) cell lines (NT-32 and NT-38). We performed a comprehensive characterization of morphology, NET differentiation, proliferation and intracellular signaling pathways of these five cell lines and, in addition, of the NT-3 GEP-NET cell line. Additionally, we conducted panel Sequencing to identify genomic alterations suitable for mutation-based targeted therapy.

Results: We found that the GEP-NEN cell lines exhibit a stable neuroendocrine phenotype. Functional kinome profiling revealed a higher activity of serine/threonine kinases (STK) as well as Protein Tyrosine Kinases (PTK) in the GEP-NET cell lines NT-3 and NT-18LM compared to the GEP-NEC cell lines NT-32 and NT-38. Panel Sequencing revealed a mutation in Death Domain Associated Protein (DAXX), sensitizing NT-18LM to the Ataxia telangiectasia and Rad3 related (ATR) inhibitor Berzosertib, and a mutation in AT-Rich Interaction Domain 1A (ARID1A), sensitizing NT-38 to the Aurora Kinase A inhibitor Alisertib. Small interfering RNA-mediated knock down of DAXX in the DAXX wild type cell line NT-3 sensitized these cells to Berzosertib.

Conclusions: The newly established GEP-NET and GEP-NEC cell lines represent comprehensive preclinical in vitro models suitable to decipher GEP-NEN biology and pathogenesis. Additionally, we present the first results of a GEP-NEN-specific mutation-based targeted therapy. These findings open up new potentialities for personalized therapies in GEP-NEN.

Keywords

ARID1A; DAXX; Mutation based targeted therapy; Neuroendocrine carcinoma; Neuroendocrine neoplasm; Neuroendocrine tumor.

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