A comparative genomic approach for identifying synthetic lethal interactions in human cancer

Raamesh Deshpande, Michael K. Asiedu, Mitchell Klebig, Shari Sutor, Elena Kuzmin, Justin Nelson, Jeff Piotrowski, Seung Ho Shin, Minoru Yoshida, Michael Costanzo, Charles Boone, Dennis A. Wigle, Chad L. Myers

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Synthetic lethal interactions enable a novel approach for discovering specific genetic vulnerabilities in cancer cells that can be exploited for the development of therapeutics. Despite successes in model organisms such as yeast, discovering synthetic lethal interactions on a large scale in human cells remains a significant challenge. We describe a comparative genomic strategy for identifying cancer-relevant synthetic lethal interactions whereby candidate interactions are prioritized on the basis of genetic interaction data available in yeast, followed by targeted testing of candidate interactions in human cell lines. As a proof of principle, we describe two novel synthetic lethal interactions in human cells discovered by this approach, one between the tumor suppressor gene SMARCB1 and PSMA4, and another between alveolar soft-part sarcoma-associated ASPSCR1 and PSMC2. These results suggest therapeutic targets for cancers harboring mutations in SMARCB1 or ASPSCR1 and highlight the potential of a targeted, cross-species strategy for identifying synthetic lethal interactions relevant to human cancer.

Original languageEnglish (US)
Pages (from-to)6128-6136
Number of pages9
JournalCancer research
Volume73
Issue number20
DOIs
StatePublished - Oct 15 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Deshpande, R., Asiedu, M. K., Klebig, M., Sutor, S., Kuzmin, E., Nelson, J., Piotrowski, J., Shin, S. H., Yoshida, M., Costanzo, M., Boone, C., Wigle, D. A., & Myers, C. L. (2013). A comparative genomic approach for identifying synthetic lethal interactions in human cancer. Cancer research, 73(20), 6128-6136. https://doi.org/10.1158/0008-5472.CAN-12-3956