Druggable Growth Dependencies and Tumor Evolution Analysis in Patient-Derived Organoids of Neuroendocrine Cancer

Dayton, T. L.; Alcala, N.; Moonen, L.; den Hartigh, L.; Mangiante, L.; Lap, L.; Dost, A. F. M.; Beumer, J.; Levy, S.; van Leeuwaarde, R. S.; Hackeng, W. M.; Samsom, K.; Voegele, C.; Sexton-Oates, A.; Begthel, H.; Korving, J.; Hillen, L.; Brosens, L. A. A.; Lantuejoul, S.; Jaksani, S.; Kok, N. F. M.; Hartemink, K. J.; Klomp, H. M.; Rinkes, I. H. M. B.; Dingemans, A.-M.; Valk, G. D.; Vriens, M. R.; Buikhuisen, W.; van den Berg, J.; Tesselaar, M.; Derks, J.; Speel, E. J.; Foll, M.; Fernandez-Cuesta, L.; Clevers, H.

doi:10.1101/2022.10.31.514549

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bioRxiv · 10.1101/2022.10.31.514549

Druggable Growth Dependencies and Tumor Evolution Analysis in Patient-Derived Organoids of Neuroendocrine Cancer

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Abstract

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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=188 HEIGHT=200 SRC="FIGDIR/small/514549v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@14bed0borg.highwire.dtl.DTLVardef@1b7791forg.highwire.dtl.DTLVardef@7120a6org.highwire.dtl.DTLVardef@116b21d_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPDTOs of pulmonary NETs and LCNEC were established C_LIO_LIPDTOs recapitulate intra-tumoral heterogeneity and evolution of parental tumors C_LIO_LIDrug assays reveal therapeutic vulnerabilities and biomarkers C_LIO_LIPulmonary NET PDTOs are dependent on EGF C_LI

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Dayton, T. L., Alcala, N., Moonen, L., den Hartigh, L., Mangiante, L., Lap, L., Dost, A. F. M., Beumer, J., Levy, S., van Leeuwaarde, R. S., Hackeng, W. M., Samsom, K., Voegele, C., Sexton-Oates, A., Begthel, H., Korving, J., Hillen, L., Brosens, L. A. A., Lantuejoul, S., Jaksani, S., Kok, N. F. M., Hartemink, K. J., Klomp, H. M., Rinkes, I. H. M. B., Dingemans, A.-M., Valk, G. D., Vriens, M. R., Buikhuisen, W., van den Berg, J., Tesselaar, M., Derks, J., Speel, E. J., Foll, M., Fernandez-Cuesta, L., Clevers, H.. 2022-11-01. Druggable Growth Dependencies and Tumor Evolution Analysis in Patient-Derived Organoids of Neuroendocrine Cancer. https://doi.org/10.1101/2022.10.31.514549

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