A Precision Oncology Approach to the Pharmacological Targeting of Mechanistic Dependencies in Neuroendocrine Tumors

Nat Genet. 2018 Jul;50(7):979-989. doi: 10.1038/s41588-018-0138-4. Epub 2018 Jun 18.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Benzamides / pharmacology
  • Cell Line, Tumor
  • Cohort Studies
  • Gastrointestinal Tract / drug effects
  • Gastrointestinal Tract / metabolism
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / metabolism
  • Humans
  • Intestinal Neoplasms / drug therapy
  • Intestinal Neoplasms / genetics
  • Neuroendocrine Tumors / drug therapy*
  • Neuroendocrine Tumors / genetics
  • Pancreas / drug effects
  • Pancreas / metabolism
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / genetics
  • Precision Medicine / methods
  • Pyridines / pharmacology
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / genetics

Substances

  • Antineoplastic Agents
  • Benzamides
  • Histone Deacetylase Inhibitors
  • Pyridines
  • entinostat
  • Histone Deacetylases

Supplementary concepts

  • Gastro-enteropancreatic neuroendocrine tumor