[Frontiers in Bioscience 14, 2904-2910, January 1, 2009]

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

Zhenyu Ji1,2, Fang C. Mei1,2, Pedro L. Lory1, Scott R. Gilbertson1, Yijun Chen3, Xiaodong Cheng1,2

1Department of Pharmacology and Toxicology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-1031,USA, 2Sealy Center for Cancer Cell Biology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-1031,USA, 3Laboratory of Chemical Biology, School of Life Science and Technology ,China Pharmaceutical University, 24 Tongjia Street, Nanjing, Jiangsu Province, 210009, People's Republic of China

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Materials and methods
3.1. Cell lines
3.2. Compound libraries
3.3. Screening
3.4. Alamar Blue cell viability assay
3.5. Data Analysis
4. Results
4.1. Oncogenic transformation of human pancreatic ductal epithelia by KRASV12
4.2. Development of a high-throughput compatible chemical genetic screen
4.3. Identification of synthetic lethal compounds selective for KRAS V12 expressing cells
5. Discussion
6. Acknowledgements
7. References

1. 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.