Overstimulation Fatal for Cancer Cells

Many cancer drugs inhibit oncogenes, but no approved therapies use the opposite strategy of overstimulating them. However, Bert O'Malley, MD, of Baylor College of Medicine in Houston, TX, and colleagues now report evidence that this counterintuitive approach may work.

The researchers were hunting for inhibitors of steroid receptor coactivators (SRC), a family of proteins that enable steroid hormone receptors such as estrogen receptor and progesterone receptor to switch on genes. SRCs benefit cancer cells by speeding growth, turning up metabolism, and promoting tissue invasion and metastasis. While performing high-throughput screening on 359,484 compounds to identify SRC inhibitors, O'Malley and his team uncovered more than 100 compounds that stimulate SRC-1, SRC-2, and SRC-3. Instead of tossing these molecules out, the researchers investigated their effects and noticed that one of them, MCB-613, killed cancer cells.

As the team reported in August, MCB-613 proved lethal in several cancer cell lines, including breast, prostate, and lung, but spared healthy cells (Cancer Cell 2015;28:240–52). MCB-613 triggered a surge in reactive oxygen species in tumor cells and initiated the unfolded protein response, a pathway that cells activate when they are under stress.

To confirm that MCB-613 works by overstimulating SRCs, the researchers measured whether the promoters for two of SRC-3′s transcriptional targets were activated. Treating tumor cells with MCB-613 dramatically increased activity of both promoters. The effect was smaller in cells with reduced levels of all three SRCs.

The two most common causes of cell death—apoptosis and autophagy—weren't responsible for the demise of the MCB-613–treated cells. Instead, O'Malley and colleagues determined that the compound triggers paraptosis, an uncommon form of cell death that can occur during embryonic development and neurodegeneration and in response to some anticancer drugs.

The researchers also tested MCB-613 in mice with breast tumors. After 7 weeks, tumor growth stalled in the 13 treated mice, whereas tumors tripled in volume in the 14 control animals.

A cancer cell can cope with the harsh conditions inside a tumor, but “it's operating at its maximum compensation in terms of stress,” says O'Malley. By boosting levels of reactive oxygen species, MCB-613 might increase the amount of stress on cancer cells and push them over the edge. The study “shows that you can kill cancer cells by overstimulating an oncogene,” he says.

Potential side effects from this approach include driving normal cells to become cancerous and increasing the aggressiveness of any tumor cells that survive the treatment. O'Malley says that his team didn't see any sign of these problems in their cell lines or animal studies.

“The concept that hyperactivation of an oncogene can be therapeutic is intriguing and worth further exploration,” says Myles Brown, MD, of Dana-Farber Cancer Institute in Boston, MA. However, he cautions that the researchers need to do more work on MCB-613 “to validate that SRCs are the only targets of its actions.”

For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.