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Cell Rep. 2016 Jun 28;16(1):133-147. doi: 10.1016/j.celrep.2016.05.063. Epub 2016 Jun 16.

In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer.

Author information

1
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.
2
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.
3
Institute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
4
Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy.
5
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
6
Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
7
Department of Epigenetics and Molecular Carcinogenesis, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
8
Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy; Department of Oncology and Hemato-oncology, University of Milan, Milan 20139, Italy.
9
Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT), Milan 20139, Italy.
10
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.
11
Department of Surgical Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
12
Department of Pathology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
13
Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
14
Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy. Electronic address: luisa.lanfrancone@ieo.eu.
15
C-4 Therapeutics, Cambridge, MA 02142, USA. Electronic address: theffernan@c4therapeutics.com.
16
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.

Abstract

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.

PMID:
27320920
DOI:
10.1016/j.celrep.2016.05.063
[Indexed for MEDLINE]
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