Researchers have 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. 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.

Drug resistance seems inevitable because tumors are constantly adapting. For over 40 years, we have been devising ways to prevent drug resistance in cancer. Their 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 signaling 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.  Reactive oxygen species are a double-edged sword in both healthy cells and in cancer cells. 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. 

One-two punch strategy

This laid the foundation for a new therapeutic strategy. Step one: Treat patients with BRAF-mutated melanoma, as usual, with signal pathway inhibitors. Step two: When the tumour has become resistant, stop giving those inhibitors and immediately treat the patients with vorinostat to kill the resistant cancer cells: a 'one-two punch' approach. A hit from the left, immediately followed by one from the right.

Getting new cancer drugs quickly and cheaply to the clinic

Bernards is happy with his scientific research, which resulted in a well-founded new strategy to treat melanoma that has become resistant. But he is at least as happy with the speed with which a lab study resulted in a clinical trial. It is unique that a clinical trial has already been part of a fundamental scientific publication. 

And moreover, Vorinostat is a notoriously expensive drug, but hospital pharmacist Beijnen can make it himself in the pharmacy of the Netherlands Cancer Institute. This is permitted for a clinical trial, and there is also no longer a patent on the American medicine.  Two follow-up studies are now planned. The first is a clinical follow-up study, under the umbrella of Oncode Institute. Bernards: "In our clinical proof-of-concept study, we gave the patients BRAF inhibitors for one year, until the cancer had become resistant.

They then exterminated the resistant cells in one month with vorinostat. Now that they know that this principle works, they want to go a step further. They are going to check the patients' blood every month for mutations in the tumor DNA.