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

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Novel preclinical gastroenteropancreatic neuroendocrine neoplasia models demonstrate the feasibility of mutation-based targeted therapy. / Viol, Fabrice; Sipos, Bence; Fahl, Martina; Clauditz, Till S; Amin, Tania; Kriegs, Malte; Nieser, Maike; Izbicki, Jakob R; Huber, Samuel; Lohse, Ansgar W; Schrader, Jörg.

In: CELL ONCOL, Vol. 45, No. 6, 12.2022, p. 1401-1419.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Viol, F, Sipos, B, Fahl, M, Clauditz, TS, Amin, T, Kriegs, M, Nieser, M, Izbicki, JR, Huber, S, Lohse, AW & Schrader, J 2022, 'Novel preclinical gastroenteropancreatic neuroendocrine neoplasia models demonstrate the feasibility of mutation-based targeted therapy', CELL ONCOL, vol. 45, no. 6, pp. 1401-1419. https://doi.org/10.1007/s13402-022-00727-z

APA

Viol, F., Sipos, B., Fahl, M., Clauditz, T. S., Amin, T., Kriegs, M., Nieser, M., Izbicki, J. R., Huber, S., Lohse, A. W., & Schrader, J. (2022). Novel preclinical gastroenteropancreatic neuroendocrine neoplasia models demonstrate the feasibility of mutation-based targeted therapy. CELL ONCOL, 45(6), 1401-1419. https://doi.org/10.1007/s13402-022-00727-z

Vancouver

Viol F, Sipos B, Fahl M, Clauditz TS, Amin T, Kriegs M et al. Novel preclinical gastroenteropancreatic neuroendocrine neoplasia models demonstrate the feasibility of mutation-based targeted therapy. CELL ONCOL. 2022 Dec;45(6):1401-1419. https://doi.org/10.1007/s13402-022-00727-z

Bibtex

@article{aa8a771889ce4bfba9ff277f857de144,
title = "Novel preclinical gastroenteropancreatic neuroendocrine neoplasia models demonstrate the feasibility of mutation-based targeted therapy",
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.",
author = "Fabrice Viol and Bence Sipos and Martina Fahl and Clauditz, {Till S} and Tania Amin and Malte Kriegs and Maike Nieser and Izbicki, {Jakob R} and Samuel Huber and Lohse, {Ansgar W} and J{\"o}rg Schrader",
note = "{\textcopyright} 2022. The Author(s).",
year = "2022",
month = dec,
doi = "10.1007/s13402-022-00727-z",
language = "English",
volume = "45",
pages = "1401--1419",
journal = "CELL ONCOL",
issn = "2211-3428",
publisher = "Springer Netherlands",
number = "6",

}

RIS

TY - JOUR

T1 - Novel preclinical gastroenteropancreatic neuroendocrine neoplasia models demonstrate the feasibility of mutation-based targeted therapy

AU - Viol, Fabrice

AU - Sipos, Bence

AU - Fahl, Martina

AU - Clauditz, Till S

AU - Amin, Tania

AU - Kriegs, Malte

AU - Nieser, Maike

AU - Izbicki, Jakob R

AU - Huber, Samuel

AU - Lohse, Ansgar W

AU - Schrader, Jörg

N1 - © 2022. The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

U2 - 10.1007/s13402-022-00727-z

DO - 10.1007/s13402-022-00727-z

M3 - SCORING: Journal article

C2 - 36269546

VL - 45

SP - 1401

EP - 1419

JO - CELL ONCOL

JF - CELL ONCOL

SN - 2211-3428

IS - 6

ER -