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Molecular and Cellular Biology, December 2006, p. 9377-9386, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.01229-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Small Interfering RNA Screens Reveal Enhanced Cisplatin Cytotoxicity in Tumor Cells Having both BRCA Network and TP53 Disruptions{triangledown} ,{ddagger}

Steven R. Bartz,1,{dagger}* Zhan Zhang,1,{dagger} Julja Burchard,1 Maki Imakura,1 Melissa Martin,1 Anthony Palmieri,1 Rachel Needham,1 Jie Guo,1 Marcia Gordon,1 Namjin Chung,2 Paul Warrener,1 Aimee L. Jackson,1 Michael Carleton,1 Melissa Oatley,2 Louis Locco,2 Francesca Santini,2 Todd Smith,2 Priya Kunapuli,2 Marc Ferrer,2 Berta Strulovici,2 Stephen H. Friend,3,4 and Peter S. Linsley1

Rosetta Inpharmatics, LLC, 401 Terry Ave N., Seattle, Washington 98109,1 Department of Automated Biotechnology, Merck Research Laboratories, Merck & Co., Inc., 502 Louise Lane, North Wales, Pennsylvania 19454,2 Departments of Advanced Technology,3 Oncology, Merck Research Labs, Merck & Co., Inc., P.O. Box 4, Sumneytown Pike, West Point, Pennsylvania 194864

Received 6 July 2006/ Returned for modification 14 August 2006/ Accepted 18 September 2006

RNA interference technology allows the systematic genetic analysis of the molecular alterations in cancer cells and how these alterations affect response to therapies. Here we used small interfering RNA (siRNA) screens to identify genes that enhance the cytotoxicity (enhancers) of established anticancer chemotherapeutics. Hits identified in drug enhancer screens of cisplatin, gemcitabine, and paclitaxel were largely unique to the drug being tested and could be linked to the drug's mechanism of action. Hits identified by screening of a genome-scale siRNA library for cisplatin enhancers in TP53-deficient HeLa cells were significantly enriched for genes with annotated functions in DNA damage repair as well as poorly characterized genes likely having novel functions in this process. We followed up on a subset of the hits from the cisplatin enhancer screen and validated a number of enhancers whose products interact with BRCA1 and/or BRCA2. TP53+/– matched-pair cell lines were used to determine if knockdown of BRCA1, BRCA2, or validated hits that associate with BRCA1 and BRCA2 selectively enhances cisplatin cytotoxicity in TP53-deficient cells. Silencing of BRCA1, BRCA2, or BRCA1/2-associated genes enhanced cisplatin cytotoxicity ~4- to 7-fold more in TP53-deficient cells than in matched TP53 wild-type cells. Thus, tumor cells having disruptions in BRCA1/2 network genes and TP53 together are more sensitive to cisplatin than cells with either disruption alone.

* Corresponding author. Mailing address: Rosetta Inpharmatics, LLC, 401 Terry Ave N., Seattle, WA 98109. Phone: (206) 802-6451. Fax: (206) 802-6388. E-mail: steven_bartz{at}merck.com.

{triangledown} Published ahead of print on 25 September 2006.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} These authors made equal contributions to the work.

Molecular and Cellular Biology, December 2006, p. 9377-9386, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.01229-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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