In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer.
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.
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy. Electronic address: acarugo@mdanderson.org.
Alessandro
A
Carugo
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Giannicola
G
Genovese
Institute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Sahil
S
Seth
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Luigi
L
Nezi
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Johnathon Lynn
JL
Rose
Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy.
Daniela
D
Bossi
Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy.
Angelo
A
Cicalese
Institute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Parantu Krushnakant
PK
Shah
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Andrea
A
Viale
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Piergiorgio Francesco
PF
Pettazzoni
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Kadir Caner
KC
Akdemir
Institute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Christopher Aaron
CA
Bristow
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Frederick Scott
FS
Robinson
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
James
J
Tepper
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Nora
N
Sanchez
Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Sonal
S
Gupta
Department of Epigenetics and Molecular Carcinogenesis, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Marcos Roberto
MR
Estecio
Institute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Virginia
V
Giuliani
Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy; Department of Oncology and Hemato-oncology, University of Milan, Milan 20139, Italy.
Gaetano Ivan
GI
Dellino
Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT), Milan 20139, Italy.
Laura
L
Riva
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Wantong
W
Yao
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Institute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Maria Emilia
ME
Di Francesco
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Tessa
T
Green
Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy.
Carolina
C
D'Alesio
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Denise
D
Corti
Department of Surgical Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Ya'an
Y
Kang
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Institute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Philip
P
Jones
Department of Pathology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Huamin
H
Wang
Department of Surgical Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Jason Bates
JB
Fleming
Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Anirban
A
Maitra
Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy; Department of Oncology and Hemato-oncology, University of Milan, Milan 20139, Italy.
Pier Giuseppe
PG
Pelicci
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Institute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Lynda
L
Chin
Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Ronald Anthony
RA
DePinho
Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy. Electronic address: luisa.lanfrancone@ieo.eu.
Luisa
L
Lanfrancone
C-4 Therapeutics, Cambridge, MA 02142, USA. Electronic address: theffernan@c4therapeutics.com.
Timothy Paul
TP
Heffernan
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Institute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: gdraetta@mdanderson.org.
Giulio Francesco
GF
Draetta
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D018450:Disease Progression; D044127:Epigenesis, Genetic; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D016086:Lentivirus / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D013312:Stress, Physiological; D023041:Xenograft Model Antitumor Assays
D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D021122:Protein Subunits; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; C502547:WDR5 protein, human; D011495:Histone-Lysine N-Methyltransferase