| Autor: |
Shereen Ezzat, Anil K. Rustgi, Stuart L. Schreiber, Kay Washington, Arul M. Chinnaiyan, Andrew L. Kung, Elena V. Komissarova, Charles Karan, Beatrice S. Knudsen, Diane Reidy-Lagunes, Daniel Diolaiti, Zhong Li, Irvin M. Modlin, Roberto Bergamaschi, Andrea Frilling, Jakob Regberg, David C. Metz, Filemon S. Dela Cruz, Deepti Dhall, Douglas A. Fraker, Emer Leahy, Ülo Langel, Ronald Realubit, Laura H. Tang, Stefano Serra, Afshin Ghavami, Prem S. Subramaniam, Antonia R. Sepulveda, Tony Detre, Lisa Bodei, Jeffrey W. Milsom, Xiaopu Yuan, Mark Kidd, Andrea Califano, Daniel Kaemmerer, Kyoung Mi Kim, Young Suk Park, Mariano J. Alvarez, Paul A. Clemons, Elizabeth A. Hagan, Robert E. Roses, Helen Remotti, Jeeyun Lee, Hai Li, Roswitha Pfragner, Massimo Barberis, Merten Hommann, Virginia A. LiVolsi, Allison R. Rainey, Michelle K. Kim, Adina Grunn, Gabrielle E. Rieckhof, Chanjuan Shi, Bertram Wiedenmann, Hee C. Kim, Dirk Jaeger, Lakshmi P. Kunju, Mahalaxmi Aburi |
| Přispěvatelé: |
Dr. Heinz-Horst Deichmann Stiftung |
| Rok vydání: |
2018 |
| Předmět: |
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| Zdroj: |
Nat Genet |
| Popis: |
We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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