title: Chemical genetic screening of KRAS-based synthetic lethal inhibitors for pancreatic cancer.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-1031, USA.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ji
authors.forename: Fang C
authors.initials: FC
authors.lastname: Mei
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Lory
authors.forename: Scott R
authors.initials: SR
authors.lastname: Gilbertson
authors.forename: Yijun
authors.initials: Y
authors.lastname: Chen
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cheng
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents