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

被引：101

作者：

Carugo, Alessandro ^{[1
,4
,9
]}

Genovese, Giannicola ^{[1
,4
]}

Seth, Sahil ^{[2
]}

Nezi, Luigi ^{[1
,4
]}

Rose, Johnathon Lynn ^{[1
,4
]}

Bossi, Daniela ^{[9
]}

Cicalese, Angelo ^{[9
]}

Shah, Parantu Krushnakant ^{[2
]}

Viale, Andrea ^{[1
,4
]}

Pettazzoni, Piergiorgio Francesco ^{[1
,4
]}

Akdemir, Kadir Caner ^{[1
]}

Bristow, Christopher Aaron ^{[2
]}

Robinson, Frederick Scott ^{[1
,4
]}

Tepper, James ^{[1
,4
]}

Sanchez, Nora ^{[1
,4
]}

Gupta, Sonal ^{[5
]}

Estecio, Marcos Roberto ^{[6
]}

Giuliani, Virginia ^{[2
]}

Dellino, Gaetano Ivan ^{[9
,10
]}

Riva, Laura ^{[11
]}

Yao, Wantong ^{[1
,4
]}

Di Francesco, Maria Emilia ^{[1
,2
]}

Green, Tessa ^{[1
,4
]}

D'Alesio, Carolina ^{[9
]}

Corti, Denise ^{[1
,4
]}

Kang, Ya'an ^{[3
]}

Jones, Philip ^{[1
,2
]}

Wang, Huamin ^{[7
]}

Fleming, Jason Bates ^{[3
]}

Maitra, Anirban ^{[5
]}

Pelicci, Pier Giuseppe ^{[9
,10
]}

Chin, Lynda ^{[1
,2
]}

DePinho, Ronald Anthony ^{[8
]}

Lanfrancone, Luisa ^{[9
]}

Heffernan, Timothy Paul ^{[12
]}

Draetta, Giulio Francesco ^{[1
,2
,4
]}

机构：

[1] UT MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[2] UT MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 USA

[3] UT MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA

[4] UT MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

[5] UT MD Anderson Canc Ctr, Sheikh Ahmed Bin Zayed Al Nahyan Ctr Pancreat Can, Houston, TX 77030 USA

[6] UT MD Anderson Canc Ctr, Dept Epigenet & Mol Carcinogenesis, Houston, TX 77030 USA

[7] UT MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[8] UT MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

[9] European Inst Oncol, Dept Expt Oncol, I-20139 Milan, Italy

[10] Univ Milan, Dept Oncol & Hematooncol, I-20139 Milan, Italy

[11] Ist Italiano Tecnol, Ctr Genom Sci IIT SEMM, I-20139 Milan, Italy

[12] C 4 Therapeut, Cambridge, MA 02142 USA

来源：

CELL REPORTS | 2016年 / 16卷 / 01期

关键词：

TUMOR-INITIATING CELLS; DNA-DAMAGE RESPONSE; H3K4; TRIMETHYLATION; RNA INTERFERENCE; C-MYC; GENES; SCREENS; REVEAL; MLL; ATR;

D O I：

10.1016/j.celrep.2016.05.063

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：133 / 147

页数：15

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