Chemical genetic screening of KRAS-based synthetic lethal inhibitors for pancreatic cancer

Front Biosci (Landmark Ed). 2009 Jan 1;14:2904-10. doi: 10.2741/3421.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Cell Line
  • Cell Transformation, Neoplastic
  • Drug Screening Assays, Antitumor
  • Genes, ras*
  • Humans
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics

Substances

  • Antineoplastic Agents