Drug Developers Looking at Synthetic Lethality in Search for Cancer Treatment

Researchers seeking to develop improved anticancer medications have adopted the principle of synthetic lethality as an approach that has already produced impressive preliminary results.

In chemotherapy, synthetic lethality refers to a combination of two or more drugs that working together kills the target tumor. While some of the individual drugs may weaken the cancer cells, none is able to kill the tumor when acting alone.

Investigators at Fox Chase Cancer Center (Philadelphia, PA, USA) began by developing a protein network centered on the epidermal growth factor receptor (EGFR), which is a validated cancer therapeutic target. They then used a literature database comprising 638 genomic "near neighbors” of EGFR to screen for drugs that would act in concert with known EGFR inhibitors. They used small inhibitory RNA (siRNA) systematically to block activity of each of the relevant genes in cultures of cancer cells that had been treated with an EGFR inhibitor.

Results published in the September 21, 2010 issue of the journal Science Signaling revealed that they ultimately identified over 60 proteins required for cell viability after treatment with an EGFR inhibitor. Blocking the gene that encoded for any of these proteins – in addition to the EGFR inhibitor – was sufficient to kill the cancer cells.

Clinically relevant drugs are already available to block some of the 60 target proteins in the EGFR network. These include inhibitors of protein kinase C, Aurora kinase A, and the transcriptional regulator signal transducer and activator of transcription 3 (STAT3). Working together with EGFR antagonists, these drugs were shown to reduce cell viability and tumor size.

"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,” said senior author Dr. Erica A Golemis, professor of cell and developmental biology at Fox Chase Cancer Center. "The most exciting hit is the Aurora kinase. Several Aurora kinase inhibitors are already being tested in the clinic and thus are available for testing in combination with EGFR inhibitors.”

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Fox Chase Cancer Center