A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Alvarez, MJ; Subramaniam, PS; Tang, LH; Grunn, A; Aburi, M; Rieckhof, G; Komissarova, EV; Hagan, EA; Bodei, L; Clemons, PA; Dela Cruz, FS; Dhall, D; Diolaiti, D; Fraker, DA; Ghavami, A; Kaemmerer, D; Karan, C; Kidd, M; Kim, KM; Kim, HC; Kunju, LP; Langel, Ü; Li, Z; Lee, J; Li, H; LiVolsi, V; Pfragner, R; Rainey, AR; Realubit, RB; Remotti, H; Regberg, J; Roses, R; Rustgi, A; Sepulveda, AR; Serra, S; Shi, C; Yuan, X; Barberis, M; Bergamaschi, R; Chinnaiyan, AM; Detre, T; Ezzat, S; Frilling, A; Hommann, M; Jaeger, D; Kim, MK; Knudsen, BS; Kung, AL; Leahy, E; Metz, DC; Milsom, JW; Park, YS; Reidy-Lagunes, D; Schreiber, S; Washington, K; Wiedenmann, B; Modlin, I; Califano, A

Published Date

  • July 2018

Published In

Volume / Issue

  • 50 / 7

Start / End Page

  • 979 - 989

PubMed ID

  • 29915428

Pubmed Central ID

  • PMC6421579

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

Digital Object Identifier (DOI)

  • 10.1038/s41588-018-0138-4


  • eng

Conference Location

  • United States