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'Synthetic lethality' strategy improves molecularly targeted cancer therapy
Date:9/21/2010

, the investigators demonstrated on three clinically relevant examples for which drugs are already availablePRKC, STAT3, and Aurora kinase Athat these proteins were necessary for cell survival in the presence of an EGFR inhibitor.

This two-hit strategywhere neither hit is adequate to kill the cells, but together they areis called synthetic lethality. Geneticists have used synthetic lethal screens in experiments with model organisms, such as fruit flies and yeast, for decades, but cancer researchers have only recently adopted the approach.

"We knew from model organisms that there was a dense network of genes. Using bioinformatics tools to intelligently mine this network provided us with a rich source of hits," says Erica A Golemis, Ph.D., professor and co-leader of the Developmental Therapeutics Program at Fox Chase, and senior author on the new study. Golemis is also co-leader of the Keystone Initiative in Head and Neck Cancer at Fox Chase, and notes that EGFR inhibitors are already broadly used in the clinic for cancers affecting the head and neck.

"The most exciting hit is the Aurora kinase," Golemis says. Several Aurora kinase inhibitors are already being tested in the clinic and thus are available for testing in combination with EGFR inhibitors.

Based on the new data, Hossein Borghaei, D.O., director of the Lung Cancer Risk Assessment Program at Fox Chase is launching a trial testing the EGFR inhibitor erlotinib with an Aurora kinase inhibitor in patients with non-small cell lung cancer. Astsaturov has started testing a drug called vandetanibwhich simultaneously inhibits EGFR and RET (another protein in the EGFR-interacting network)in patients with esophageal cancer.

In addition to providing a rich source of synthetic lethal hits, limiting the siRNA screen to a previously-defined network of interacting proteins had an important impact on the size of the project, according to Golemis. "A full genome siRNA screen is pr
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Contact: Diana Quattrone
Diana.Quattrone@fccc.edu
215-728-7784
Fox Chase Cancer Center
Source:Eurekalert

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