A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors.
Mariano J AlvarezPrem S SubramaniamLaura H TangAdina GrunnMahalaxmi AburiGabrielle RieckhofElena V KomissarovaElizabeth A HaganLisa BodeiPaul A ClemonsFilemon S Dela CruzDeepti DhallDaniel DiolaitiDouglas A FrakerAfshin GhavamiDaniel KaemmererCharles KaranMark KiddKyoung M KimKyoung-Mee KimLakshmi P KunjuÜlo LangelZhong LiJeeyun LeeHai LiVirginia LiVolsiRoswitha PfragnerAllison R RaineyRonald B RealubitHelen RemottiJakob RegbergRobert RosesAnil RustgiAntonia R SepulvedaStefano SerraChanjuan ShiXiaopu YuanMassimo BarberisRoberto BergamaschiArul M ChinnaiyanTony DetreShereen EzzatAndrea FrillingMerten HommannDirk JaegerMichelle K KimBeatrice S KnudsenAndrew L KungEmer LeahyDavid C MetzJeffrey W MilsomYoung S ParkDiane Reidy-LagunesStuart SchreiberKay WashingtonBertram WiedenmannIrvin ModlinAndrea CalifanoPublished in: Nature genetics (2018)
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.
Keyphrases
- neuroendocrine tumors
- end stage renal disease
- newly diagnosed
- ejection fraction
- palliative care
- transcription factor
- chronic kidney disease
- single cell
- small cell lung cancer
- squamous cell carcinoma
- stem cells
- prognostic factors
- peritoneal dialysis
- patient reported outcomes
- induced apoptosis
- high throughput
- bone marrow
- genome wide
- cancer therapy
- mesenchymal stem cells
- cell therapy
- quality improvement
- endoplasmic reticulum stress
- cell death
- data analysis
- electronic health record