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

Cell Oncol (Dordr). 2022 Dec;45(6):1401-1419. doi: 10.1007/s13402-022-00727-z. Epub 2022 Oct 21.

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.

MeSH terms

  • Feasibility Studies
  • Humans
  • Intestinal Neoplasms* / drug therapy
  • Intestinal Neoplasms* / genetics
  • Intestinal Neoplasms* / pathology
  • Mutation / genetics
  • Neuroendocrine Tumors* / drug therapy
  • Neuroendocrine Tumors* / genetics
  • Neuroendocrine Tumors* / metabolism
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / metabolism
  • Stomach Neoplasms* / drug therapy
  • Stomach Neoplasms* / genetics
  • Stomach Neoplasms* / pathology

Supplementary concepts

  • Gastro-enteropancreatic neuroendocrine tumor