Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma

2018 ◽  
Vol 41 (10) ◽  
pp. 619-625 ◽  
Author(s):  
Anna Schmitt ◽  
Georg Feldmann ◽  
Thomas Zander ◽  
H. Christian Reinhardt
Keyword(s):  
Dna Damage ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Dna Damage Response ◽  
Ductal Adenocarcinoma ◽  
Damage Response ◽  
Cellular Dna

scholarly journals Disruption of FDPS/Rac1 axis radiosensitizes pancreatic ductal adenocarcinoma by attenuating DNA damage response and immunosuppressive signalling

EBioMedicine ◽  
2022 ◽  
Vol 75 ◽  
pp. 103772
Author(s):  
Parthasarathy Seshacharyulu ◽  
Sushanta Halder ◽  
Ramakrishna Nimmakayala ◽  
Satyanarayana Rachagani ◽  
Sanjib Chaudhary ◽  
...  
Keyword(s):  
Dna Damage ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Dna Damage Response ◽  
Ductal Adenocarcinoma ◽  
Damage Response

scholarly journals PET Imaging of DNA Damage Response following 225Ac-radioimmunotherapy in a Pancreatic Ductal Adenocarcinoma Mouse Model

2019 ◽  
Vol 50 (1) ◽  
pp. S4-S5
Author(s):  
Sophie Poty ◽  
James C. Knight ◽  
Patrick Donabedian ◽  
Komal Mandleywala ◽  
Bart Cornelissen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mouse Model ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Dna Damage Response ◽  
Pet Imaging ◽  
Ductal Adenocarcinoma ◽  
Damage Response

PET Imaging of DNA Damage Response following 225Ac-radioimmunotherapy in a Pancreatic Ductal Adenocarcinoma Mouse Model

2019 ◽  
Vol 50 (4) ◽  
pp. S70
Author(s):  
Sophie Poty ◽  
James C. Knight ◽  
Patrick Donabedian ◽  
Komal Mandleywala ◽  
Bart Cornelissen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mouse Model ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Dna Damage Response ◽  
Pet Imaging ◽  
Ductal Adenocarcinoma ◽  
Damage Response

scholarly journals PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Virginia Giuliani ◽  
Meredith A. Miller ◽  
Chiu-Yi Liu ◽  
Stella R. Hartono ◽  
Caleb A. Class ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Growth ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Dna Damage Response ◽  
Rna Splicing ◽  
Rna Metabolism ◽  
Arginine Methylation ◽  
Ductal Adenocarcinoma ◽  
Damage Response

AbstractPancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development.Statement of significancePDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors.

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