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Torchia, Jonathon; Golbourn, Brian; Ho, King Ching; Sin-Chan, Patrick; Vasiljevic, Alexandre; Norman, Joseph D.; Guilhamon, Paul; Garzia, Livia; Agamez, Natalia R.; Chan, Tiffany S.; Picard, Daniel; de Antonellis, Pasqualino; Khuong-Quang, Dong-Anh; Planello, Aline C.; Zeller, Constanze; Barsyte-Lovejoy, Dalia; Lafay-Cousin, Lucie; Letourneau, Louis; Bourgey, Mathieu; Yu, Man; Dzamba, Misko; Barszczyk, Mark; Medina, Tiago; Riemenschneider, Alexandra N.; Morrissy, A. Sorana; Ra, Young-Shin; Ramaswamy, Vijay; Remke, Marc; Dunham, Christopher P.; Yip, Stephen; Ng, Ho-keung; Lu, Jian-Qiang; Mehta, Vivek; Albrecht, Steffen; Pimentel, Jose; Chan, Jennifer A.; Somers, Gino R.; Faria, Claudia C.; Roque, Lucia; Fouladi, Maryam; Moore, Andrew S.; Wang, Yin; Hansford, Jordan R.; Catchpoole, Daniel; Birks, Diane K.; Foreman, Nicholas K.; Strother, Doug; Klekner, Almos; Bognár, Laszló; Garami, Miklós; Hauser, Péter; Hortobágyi, Tibor; Wilson, Beverly; Hukin, Juliette; Carret, Anne-Sophie; Van Meter, Timothy E.; Hwang, Eugene I.; Gajjar, Amar; Chiou, Shih-Hwa; Toledano, Helen; Fults, Daniel; Wataya, Takafumi; Fryer, Chris; Eisenstat, David D.; Fleming, Adam J.; Johnston, Donna L.; Michaud, Jean; Hammond, Robert; Afzal, Samina; Ramsay, David A.; Sirachainan, Nongnuch; Hongeng, Suradej; Larbcharoensub, Noppadol; Grundy, Richard G.; Fangusaro, Jason R.; Druker, Harriet; Bartels, Ute; Grant, Ronald; Malkin, David; Nicolaides, Theodore; Tihan, Tarik; Majewski, Jacek; Bourque, Guillaume; Bader, Gary D.; Gillespie, G. Yancey; Warmuth-Metz, Monika; Rutkowski, Stefan; Tabori, Uri; Lupien, Mathieu; Pietsch, Torsten; Hawkins, Cynthia E.; Bouffet, Eric; Dirks, Peter B.; Taylor, Michael D.; Erdreich-Epstein, Anat; Arrowsmith, Cheryl H.; De Carvalho, Daniel D.; Rutka, James T.; Jabado, Nada; Huang, Annie
Cancer cell, 12/2016, Letnik: 30, Številka: 6Journal Article
We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype. Display omitted •ATRTs comprise three molecular and epigenetic subgroups: group 1, 2A, and 2B•Distinct chromatin landscape drives subgroup-specific lineage and signaling features•ATRT subgroups exhibit distinct sensitivity to signaling and epigenetic inhibitors•Epigenetically regulated PDGFRB enhancer drives TKI sensitivity in group 2 ATRTs Torchia et al. show that atypical teratoid rhabdoid tumors (ATRTs) are composed of three epigenetic subgroups that correlate with differential cellular responses to a panel of signaling and epigenetic inhibitors. Specifically, dasatinib and nilotinib are identified as promising therapeutics for group 2 ATRTs.
