RT Journal Article
SR Electronic
T1 Targeted CRISPR screening identifies PRMT5 as synthetic lethality combinatorial target with gemcitabine in pancreatic cancer cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.25.112896
DO 10.1101/2020.05.25.112896
A1 Xiaolong Wei
A1 Jiekun Yang
A1 Sara J. Adair
A1 Cem Kuscu
A1 Kyung Yong Lee
A1 William Kane
A1 Patrick O’hara
A1 Denis Liu
A1 Yusuf Mert Demirlenk
A1 Alaa Hamdi Habieb
A1 Ebru Yilmaz
A1 Anindya Dutta
A1 Todd W. Bauer
A1 Mazhar Adli
YR 2020
UL http://biorxiv.org/content/early/2020/05/26/2020.05.25.112896.abstract
AB Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging cancer to treat. Due to the asymptomatic nature of the disease and ineffective drug treatment modalities, the survival rate of PDAC patients remains one of the lowest. The recurrent genetic alterations in PDAC are yet to be targeted; therefore, identifying effective therapeutic combinations is desperately needed. Here, we performed an in vivo CRISPR screening in a clinically relevant patient-derived xenograft (PDX) model system to identify synergistic drug combinations for PDAC treatment. Our approach revealed protein arginine methyltransferase gene 5 (PRMT5) as a promising druggable candidate whose inhibition creates synergistic vulnerability of PDAC cells to gemcitabine. Genetic and pharmacological inhibition results indicate that of PRMT5 depletion results in synergistic cytotoxicity with Gem due to depleted replication protein A (RPA) levels and an impaired non-homology end joining (NHEJ) DNA repair. Thus, the novel combination creates conditional lethality through the accumulation of excessive DNA damage and cell death, both in vitro and in vivo. The findings demonstrate that unbiased genetic screenings combined with a clinically relevant model system is an effective approach in identifying synthetic lethal drug combinations for cancer treatment.STATEMENT of SIGNIFICANCE Identify synergistic drug combinations for PDAC is a significant unmet need. Through CRISPR screening, we discovered and validated that PRMT5 depletion creates synergistic vulnerability of PDAC cells to gemcitabine. Mechanistically, the combination impairs DNA repair, synergistic accumulation of DNA damage and cell death in vitro and in vivo.Competing Interest StatementThe authors have declared no competing interest.