Research provides new knowledge about melanoma.

Study points to most effective combination of drugs against resistant cancer.

New research from the Danish Cancer Institute provides knowledge about a chain reaction inside of melanoma cancer cells that can make them resistant to treatment. The new results may lay the foundation for new and better treatments for patients.

The long-term perspectives in our research are that by measuring the amount of a single protein, AMBRA1, you can determine which treatment is the most effective for the individual patient. There is even the possibility that we can offer treatment that works against cancer that has otherwise become resistant to the treatments we have today, explains team leader Daniela De Zio from the research group The Melanoma Research Team, at The Danish Cancer Institute.

Showing the way to resistant cancer

Today, treatment against melanoma is typically chosen based on the genetic changes the cancer cells have. An example is medication of the type MAP kinase inhibitors. It works against a particular genetic change that around half of all cancer patients with melanoma have.

A major challenge in the treatment, however, is that the cancer cells run the risk of becoming resistant to the treatment over time.

But the new research shows that the amount of the protein AMBRA1 influences whether the cancer cells become resistant to treatment with MAP kinase inhibitors. More precisely, low levels of AMBRA1 lead to an activation of the protein FAK1 – and this makes the cancer cells resistant to the MAP kinase inhibitors.

Testing new combinations of medications

The researchers have investigated how the new knowledge can be used in the treatment. They have treated cancer cells that have different levels of AMBRA1 with MAP kinase inhibitors, as well as with drugs that inhibit FAK1.

The various combinations can be a little complicated to follow, but Daniela De Zio summarizes the results:

We show that AMBRA1 can be used as a marker that can show the way to the best treatment. If the amount of AMBRA1 is low, our results show that FAK1 inhibitors are most effective. If the amount of AMBRA1 is high, according to our results, it is most effective to combine MAP kinase inhibitors and FAK1 inhibitors - especially since this will prevent the development of resistance to the treatment, says Daniela De Zio.

Drugs against FAK1 are not yet approved for the treatment of melanoma, but clinical trials are ongoing to test their effect on patients.

Hope for new treatments

The research has so far only been carried out in the laboratory, but the researchers hope that in time it may have an impact on the treatment offered to patients with melanoma.

The experiments showed that in cancer cells with low levels of AMBRA1, MAP kinase inhibitors had no effect. In contrast, agents that inhibited FAK1 could kill the cancer cells.

In cancer cells with high amounts of AMBRA1, MAP kinase inhibitors worked for a period, but then many of the cancer cells became resistant to the treatment, just as you can risk seeing in patients. But if you combined MAP kinase inhibitors and FAK1 inhibitors from the start, no resistant cancer cells were developed – and all the cells died.

The results are published here: Di Leo L. et al.: AMBRA1 levels predict resistance to MAPK inhibitors in melanoma. PNAS