Chemical genetic screening of KRAS-based synthetic lethal inhibitors for pancreatic cancer.
Pancreatic cancer is one of the deadliest diseases largely due to difficulty in early diagnosis and the lack of effective treatments. KRAS is mutated in more than 90% of pancreatic cancer patients, and oncogenic KRAS contributes to pancreatic cancer tumorigenesis and progression. In this report, using an oncogenic KRASV12-based pancreatic cancer cell model, we developed a chemical genetic screen to identify small chemical inhibitors that selectively target pancreatic cancer cells with gain-of-function KRAS mutation. After screening ~3,200 compounds, we identified one compound that showed selective synthetic lethality against the KRASV12 transformed human pancreatic ductal epithelial cell over its isogenic parental cell line. These selective KRASV12-synthetic lethal compounds may serve as leads for subsequent development of clinically-effective treatments for pancreatic cancer.
Ji
Zhenyu
Z
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-1031, USA.
Mei
Fang C
FC
Lory
Pedro L
PL
Gilbertson
Scott R
SR
Chen
Yijun
Y
Cheng
Xiaodong
X
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004354:Drug Screening Assays, Antitumor; D011905:Genes, ras; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics
D000970:Antineoplastic Agents