Shooting the Achilles heel of drug-resistant cancer

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Cancer cells that develop resistance to drugs pay a price for this, by simultaneously developing a new vulnerability. If this acquired vulnerability can be identified, it may be exploited clinically. A team of cancer researchers, led by Rene Bernards of the Netherlands Cancer Institute and Oncode Institute, now exposed this acquired vulnerability in melanoma that has developed resistance to a targeted therapy with BRAF-inhibitors. The team then developed a new therapeutic strategy to selectively kill the drug-resistant cancer cells.

One of the greatest obstacles in treating cancer is the rapid emergence of therapy resistance. However, when cancer cells develop drug resistance, they also acquire a new vulnerability, which is, in Darwinian terms, the fitness cost that comes with adapting to a new regime. If this newly acquired vulnerability can be exposed, it may be exploited clinically to keep the cancer at bay for a longer period, according to cancer researcher Rene Bernards.

Professor Bernards said, “Drug resistance seems inevitable because tumours are constantly adapting. For over 40 years, we have been devising ways to prevent drug resistance in cancer. Now I think: let’s just accept that this is the way it is, and go and see if we can find the new vulnerability associated with resistance. Then we can exploit this sensitivity clinically and keep the cancer under control for a longer time.”

Bernards and his team were able to expose this new vulnerability in melanoma that has developed resistance to treatment with a BRAF inhibitor: a targeted therapy that blocks a signalling pathway in the cancer cell through which it gets the message to keep on dividing. This is due to a mutation in the BRAF gene, which plays an important role in cell division in healthy cells.

More than half of all melanoma patients have a mutation in this BRAF gene. For these people, the BRAF-inhibitor does its job and tumour growth stops. But within a few months the tumour cell adapts the original signalling pathway becomes active again, and even hyperactive, so that all lights are green to start growing again.

The key question is: what price does melanoma pay for resistance? In the lab, the researchers made melanoma cells resistant to the BRAF inhibitor and saw that the hyperactive resistant melanoma cells produced large amounts of reactive oxygen species. Cancer cells that were still sensitive to the drug did not do this.

Reactive oxygen species are – both in healthy cells and in cancer cells – a double-edged sword. They play an important role in transmitting signals in the cell, but if their concentration becomes too high, they cause DNA damage and the cell may stop dividing. Also in the Bernards experiment, the abundance of free radicals caused the resistant melanoma cells to stop dividing. However: they did not die.

Bernards explained, “Then we thought: suppose we can give those hyperactive resistant tumour cells the last push towards cell death, by allowing them to produce even more free radicals.” In the lab, this worked perfectly by exposing the cells to a substance that stimulates the production of free oxygen radicals. Only the resistant tumour cells died; tumour cells that were still sensitive to the original drug remained alive.