Researchers have discovered that a particular drug combination may have a more significant effect against melanoma, a type of cancer that typically occurs in the skin, than other medications.

According to recent studies, one of the best ways of blocking melanoma is by administering protein kinase inhibitors, which prevent the action of certain specialized enzymes.

The main downside of treating people with this type of cancer with protein kinase inhibitors is that they often acquire resistance to the drugs, making them ineffective.

However, researchers from the Massachusetts Institute of Technology in Cambridge, believe they may have found a way to boost the effect of protein kinase inhibitors and prevent resistance to them.

The specialists suggest that combining protein kinase inhibitors with ribonuclease drugs could improve melanoma treatment.

Ribonucleases can "unravel" RNA, a molecule that helps to encode and decode genes, as well as regulate gene expression. They also put up a "shield" against viral RNA, which is the genetic material of certain aggressive viruses.

"We discovered that this ribonuclease drug could be paired favorably with other cancer chemotherapeutic agents, and not only that, the pairing made logical sense in terms of the underlying biochemistry," explains Prof. Ronald Raines, senior author of the new study.

The researchers report their findings in the current issue of the Molecular Cancer Therapeutics journal.

Coming up with a new drug

Prof. Raines and the researchers working in his laboratory have been studying ribonucleases for about 20 years, with the aim of producing a new cancer drug.

At the same time, the research team has also been studying the "ribonuclease inhibitor," which is the protein that blocks ribonucleases. These proteins negatively affect cells if their activity is not limited.

The ribonuclease inhibitor bound to ribonuclease had a half-life (measurement of how long a substance can maintain its activity) of at least 3 months, Prof. Raines explains.

"That means that should ribonuclease invade cells, there is an unbelievable defense system," he adds.

To create a ribonuclease anti-cancer drug that they could test in trials, the researchers altered ribonuclease so that its inhibitors would bind less tightly to it, giving the bound molecules a half-life of just a few seconds.

The team explains that in a phase 1 clinical trial, the ribonuclease drug has successfully stabilized cancer in approximately 20% of participants.

'Fortuitous intersection of 2 strategies'

In the current study, the researchers decided to develop the ribonuclease inhibitor in human cells rather than in Escherichia coli (E. coli), which had been their approach up until that point.

The researchers found that this version could establish bonds that were 100 times stronger than the inhibitors produced in E. coli, though the proteins were structurally identical.

When they looked into why the ribonuclease inhibitors produced in human cells established such tight bonds, the investigators found that they had additional phosphate groups, which attach through a process known as "phosphorylation," and which seemed to give them the extra strength.

Moreover, the phosphorylation occurred thanks to the action of protein kinases, which form part of a signaling pathway dubbed "ERK," which also happens to be overactive in many cancer cells.

Two protein kinase inhibitors used in the treatment of melanoma—trametinib and dabrafenib—can block this pathway. These observations allowed the researchers to find the link between ribonucleases and protein kinases, which suggests a new, double line of attack against cancer.

"This was a fortuitous intersection of two different strategies because we reasoned that if we could use these drugs to deter the phosphorylation of ribonuclease inhibitor, then we could make the ribonucleases more potent at killing cancer cells."

—Prof. Ronald Raines

A promising new approach

When testing this hypothesis in human melanoma cells, the researchers found that they were on the right path. A combination of kinase inhibitors and ribonuclease was more effective against cancer cells, and the researchers administered them at lower concentrations.

The kinase inhibitor stopped the phosphorylation of ribonuclease, both facilitating its activity against RNA, and rendering it less potentially harmful to cell health.

Eventually, the investigators aim to test this approach in people with cancer, hoping that the new drug combo will prevent cancer tumors from becoming treatment-resistant. The first step, however, will be to test the combination in a mouse model.

The team has also genetically engineered a group of mice that do not produce ribonucleases. They aim to use the mice to gain a better understanding of how ribonucleases naturally work.

"We're hoping that we can explore relationships with some of the many pharmaceutical companies that develop ERK pathway inhibitors, to team up and use our ribonuclease drug in concert with kinase inhibitors," says Prof. Raines.