SUMMARY
Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors and poorly-differentiated carcinomas. Treatment options for patients with NENs are limited, in part due to lack of accurate models. To address this need we established the first patient-derived tumor organoids (PDTOs) from pulmonary neuroendocrine tumors and derived PDTOs from an understudied NEN subtype, large cell neuroendocrine carcinoma (LCNEC). PDTOs maintain the gene expression patterns, intra-tumoral heterogeneity, and evolutionary processes of parental tumors. Through drug sensitivity analyses, we uncover therapeutic sensitivities to an inhibitor of NAD salvage biosynthesis and to an inhibitor of BCL-2. Finally, we identify a dependency on EGF in pulmonary neuroendocrine tumor PDTOs. Consistent with these findings, analysis of an independent cohort showed that approximately 50% of pulmonary neuroendocrine tumors expressed EGFR. This study identifies a potentially actionable vulnerability for a subset of NENs, and further highlights the utility of these novel PDTO models for the study of NENs.
Highlights
PDTOs of pulmonary NETs and LCNEC were established
PDTOs recapitulate intra-tumoral heterogeneity and evolution of parental tumors
Drug assays reveal therapeutic vulnerabilities and biomarkers
Pulmonary NET PDTOs are dependent on EGF
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
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In brief Novel patient-derived tumor organoid models reveal a targetable growth-factor dependency in a subset of pulmonary neuroendocrine tumors and serve as a platform for neuroendocrine cancer research