Synthetic lethal RNAi screening identifies sensitizing targets for gemcitabine therapy in pancreatic cancer
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BioMed Central
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Synthetic lethal RNAi screening identifies sensitizing targets for gemcitabine therapy in pancreatic cancer David O Azorsa*1, Irma M Gonzales1, Gargi D Basu1, Ashish Choudhary1, Shilpi Arora1, Kristen M Bisanz1, Jeffrey A Kiefer1, Meredith C Henderson1, Jeffrey M Trent2, Daniel D Von Hoff3 and Spyro Mousses1 Address: 1Pharmaceutical Genomics Division, The Translational Genomics Research Institute, Scottsdale, Arizona 85259, USA, 2Genetic Basis of Human Disease Division, The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA and 3Clinical Translational Research Division, The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA Email: David O Azorsa* - [email protected]; Irma M Gonzales - [email protected]; Gargi D Basu - [email protected]; Ashish Choudhary - [email protected]; Shilpi Arora - [email protected]; Kristen M Bisanz - [email protected]; Jeffrey A Kiefer - [email protected]; Meredith C Henderson - [email protected]; Jeffrey M Trent - [email protected]; Daniel D Von Hoff - [email protected]; Spyro Mousses - [email protected] * Corresponding author
Published: 11 June 2009 Journal of Translational Medicine 2009, 7:43
doi:10.1186/1479-5876-7-43
Received: 12 March 2009 Accepted: 11 June 2009
This article is available from: http://www.translational-medicine.com/content/7/1/43 © 2009 Azorsa et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Background: Pancreatic cancer retains a poor prognosis among the gastrointestinal cancers. It affects 230,000 individuals worldwide, has a very high mortality rate, and remains one of the most challenging malignancies to treat successfully. Treatment with gemcitabine, the most widely used chemotherapeutic against pancreatic cancer, is not curative and resistance may occur. Combinations of gemcitabine with other chemotherapeutic drugs or biological agents have resulted in limited improvement. Methods: In order to improve gemcitabine response in pancreatic cancer cells, we utilized a synthetic lethal RNAi screen targeting 572 known kinases to identify genes that when silenced would sensitize pancreatic cancer cells to gemcitabine. Results: Results from the RNAi screens identified several genes that, when silenced, potentiated the growth inhibitory effects of gemcitabine in pancreatic cancer cells. The greatest potentiation was shown by siRNA targeting checkpoint kinase 1 (CHK1). Validation of the screening results was performed in MIA PaCa-2 and BxPC3 pancreatic cancer cells by examining the dose response of gemcitabine treatment in the presence of either CHK1 or CHK2 siRNA. These results showed a three to ten-fold decrease in the EC50 for CHK1 siRNA-treated cells versus control siRNA-treated cells while treatment with CHK2 siRNA resulted in n
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