ABSTRACT
There are no therapeutic predictive biomarkers or representative preclinical models for high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), a highly aggressive, fatal, and heterogeneous epithelial malignancy. We established patient-derived (PD) tumoroids from biobanked tissue samples of advanced high-grade GEP-NEN patients and applied this model for targeted rapid ex vivo pharmacotyping, next-generation sequencing, and perturbational profiling. We used tissue-matched PD tumoroids to profile individual patients, compared ex vivo drug response to patients’ clinical response to chemotherapy, and investigated treatment-induced adaptive stress responses.
PD tumoroids recapitulated biological key features of high-grade GEP-NEN and mimicked clinical response to cisplatin and temozolomide ex vivo. When we investigated treatment-induced adaptive stress responses in PD tumoroids in silico, we discovered and functionally validated Lysine demethylase 5A and interferon-beta, which act synergistically in combination with cisplatin. Since ex vivo drug response in PD tumoroids matched clinical patient responses to standard-of-care chemotherapeutics for GEP-NEN, our rapid and functional precision oncology approach could expand personalized therapeutic options for patients with advanced high-grade GEP-NEN.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Financial support The study was supported by the Swiss Cancer Research Foundation to A.P. (KFS-4227-08-2017) and Wilhelm Sander to I.M. and a generous donation by Dr. M. Gunzenhauser and B. Piepgras to B. W.
Conflict of interest disclosure statement The authors declare no potential conflicts of interest.
Affiliations; Co-author list; SciScore; Improvment in figure size and figure legends and minor adaptions of preliminary data; Due to file size limitations a high resolution version of the manuscript and figures is available on request
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE213504
