New Research Targets Myc-Driven Cancers

Myc DNA Complex, New Research Targets Myc-Driven Cancers

New research in the fight against breast cancer and prostate cancer could produce positive results. Researchers discovered a way to stop Myc-driven cancer cells by inhibiting helper genes instead of targeting the oncogene directly.

Researchers have found a way to kill human cells hijacked by a genetic accelerator that puts cancer cells into overdrive: the Myc oncogene. The discovery reveals new drug targets for Myc-driven cancers, which tend to be particularly aggressive.

The results were published online December 8 in Science.

In its non-cancerous, healthy form, Myc oversees how genetic information is translated into proteins, typically those involved in growing new cells. But mutations can cause Myc to become hyper-activated, or oncogenic, and when that happens, cells divide uncontrollably and form tumors.

Myc-dependent cancer cells are addicted to the oncogene, to the extent that they’ll die if it’s disabled. Scientists have long tried to exploit this vulnerability in drug development. However, in its protein form, Myc is a notoriously difficult target, mainly because it lacks efficient binding sites for drug compounds.

So Stephen Elledge, a professor in the Department of Genetics at Harvard Medical School, and a senior author on the paper, and his collaborator and co-senior author Thomas Westbrook, an assistant professor at the Baylor College of Medicine, opted for a different approach. They aimed to suppress Myc by disabling its helper genes rather than the oncogene itself. Taking advantage of “synthetic lethality,” or the cell-killing effect of having two incompatible mutations in a shared pathway, they hoped to mimic the success seen in studies of genes associated with inherited breast cancer.

To find the genes, Elledge and Westbrook used a method that relies on tiny RNA molecules (dubbed short-hairpin RNA or shRNAs) that block the activity of specified genes. The scientists used those shRNAs in experiments with human breast epithelial cells in which Myc could be selectively hyper-activated. Each cell in the experiment contained just one silenced gene. If the cell died when Myc’s cancer activity was triggered, then that silenced gene was clearly one Myc needed to form tumors.

Altogether they tested nearly 75,000 shRNAs, and ultimately found 403 potential candidates; some familiar to the field of Myc biology and some not. “These genes aren’t oncogenes in and of themselves, but they do code for proteins that Myc relies on to cause cancer,” said Elledge, who is also a professor of medicine at Brigham and Women’s Hospital. “We see them as potential targets for drug therapy—even if you can’t target Myc, you can target these other genes and inactivate its effects.”





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