TY - JOUR
T1 - In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer
AU - Carugo, Alessandro
AU - Genovese, Giannicola
AU - Seth, Sahil
AU - Nezi, Luigi
AU - Rose, Johnathon Lynn
AU - Bossi, Daniela
AU - Cicalese, Angelo
AU - Shah, Parantu Krushnakant
AU - Viale, Andrea
AU - Pettazzoni, Piergiorgio Francesco
AU - Akdemir, Kadir Caner
AU - Bristow, Christopher Aaron
AU - Robinson, Frederick Scott
AU - Tepper, James
AU - Sanchez, Nora
AU - Gupta, Sonal
AU - Estecio, Marcos Roberto
AU - Giuliani, Virginia
AU - Dellino, Gaetano Ivan
AU - Riva, Laura
AU - Yao, Wantong
AU - Di Francesco, Maria Emilia
AU - Green, Tessa
AU - D'Alesio, Carolina
AU - Corti, Denise
AU - Kang, Ya'an
AU - Jones, Philip
AU - Wang, Huamin
AU - Fleming, Jason Bates
AU - Maitra, Anirban
AU - Pelicci, Pier Giuseppe
AU - Chin, Lynda
AU - DePinho, Ronald Anthony
AU - Lanfrancone, Luisa
AU - Heffernan, Timothy Paul
AU - Draetta, Giulio Francesco
N1 - Publisher Copyright:
© 2016
PY - 2016/6/1
Y1 - 2016/6/1
N2 - Current treatment regimens for pancreatic ductal adenocarcinoma (PDAC) yield poor 5-year survival, emphasizing the critical need to identify druggable targets essential for PDAC maintenance. We developed an unbiased and in vivo target discovery approach to identify molecular vulnerabilities in low-passage and patient-derived PDAC xenografts or genetically engineered mouse model-derived allografts. Focusing on epigenetic regulators, we identified WDR5, a core member of the COMPASS histone H3 Lys4 (H3K4) MLL (1–4) methyltransferase complex, as a top tumor maintenance hit required across multiple human and mouse tumors. Mechanistically, WDR5 functions to sustain proper execution of DNA replication in PDAC cells, as previously suggested by replication stress studies involving MLL1, and c-Myc, also found to interact with WDR5. We indeed demonstrate that interaction with c-Myc is critical for this function. By showing that ATR inhibition mimicked the effects of WDR5 suppression, these data provide rationale to test ATR and WDR5 inhibitors for activity in this disease.
AB - Current treatment regimens for pancreatic ductal adenocarcinoma (PDAC) yield poor 5-year survival, emphasizing the critical need to identify druggable targets essential for PDAC maintenance. We developed an unbiased and in vivo target discovery approach to identify molecular vulnerabilities in low-passage and patient-derived PDAC xenografts or genetically engineered mouse model-derived allografts. Focusing on epigenetic regulators, we identified WDR5, a core member of the COMPASS histone H3 Lys4 (H3K4) MLL (1–4) methyltransferase complex, as a top tumor maintenance hit required across multiple human and mouse tumors. Mechanistically, WDR5 functions to sustain proper execution of DNA replication in PDAC cells, as previously suggested by replication stress studies involving MLL1, and c-Myc, also found to interact with WDR5. We indeed demonstrate that interaction with c-Myc is critical for this function. By showing that ATR inhibition mimicked the effects of WDR5 suppression, these data provide rationale to test ATR and WDR5 inhibitors for activity in this disease.
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U2 - 10.1016/j.celrep.2016.05.063
DO - 10.1016/j.celrep.2016.05.063
M3 - Article
C2 - 27320920
AN - SCOPUS:85008397717
SN - 2211-1247
VL - 16
SP - 133
EP - 147
JO - Cell Reports
JF - Cell Reports
IS - 1
ER -