Myc mac, cancer whack. Researchers have discovered a new way to defeat one of the most sinister genes in cancer biology. Reporting today in Science, a US team showed that hitting one of the molecular helpers of the Myc oncogene, rather than going directly after the elusive cancer target itself, offers a promising new therapeutic strategy for stopping aggressive tumors.
In its mutated form, Myc drives cells to frenzied, uncontrollable growth, leading to aggressive tumor formation. Cancer biologists have long searched for drugs that can silence the transcription factor encoded by Myc, but the cancer-causing protein has proven to be a slippery foe. “There is a striking lack of Myc-directed therapeutics despite 30 years of data pointing to Myc as a target for therapy,” says James Bradner, a medical oncologist at the Dana-Farber Cancer Institute in Boston who was not involved in the latest study.
Because Myc itself is so difficult to target, cancer researchers have begun to consider indirect tactics. Bradner last year developed a small molecule targeting the ‘bromodomain’ protein BRD4, which interacts alongside Myc. Widespread investigation of Bradner’s BRD4 inhibitor over the last ten months has shown it to be successful in halting Myc-dependent cancers in the blood. However, bromodomain inhibitors do not show as much promise when applied to Myc-dependent cancers in solid organs. Meanwhile, other groups have taken a different tack, trying to identify Myc coactivator proteins.
Most recently, Stephen Elledge, a geneticist at the Harvard Medical School in Boston, and his former postdoc Thomas Westbrook, now at the Baylor College of Medicine in Houston, identified the SUMO-activating-enzyme 2 (SAE2) as a protein to which Myc is hopelessly addicted. Using an shRNA screen, they identified SAE2 and subsequently knocked the gene out in breast cancer cells, showing that Myc-dependent cancer cells also depend on SAE2.
“We found right off the bat that if you inhibit SAE2 is cancer cells that depend on Myc, the cells die,” Elledge explains. The researchers further investigated SAE2 by stratifying gene expression data from around 1,300 women with breast cancer, and showed the people with high Myc activity had a lower instances of metastatic cancer and death if they had naturally low SAE2 levels. (SAE2 levels didn’t matter for those with low Myc activity.)
“Inhibiting Myc coactivator proteins is a very fruitful path to take to attack cancers with high Myc activity,” says Bradner.
Although the researchers have not yet found a drug that can target SAE2, Elledge expects that wiping out SAE2 could cause tumor cells to fall flat on their faces, so to speak. “Everyone thinks cancer cells are super cells, but they’re really very sick cells, limping forward on crutches,” he says. “SAE2 is one of those crutches.”