Dutch scientists suggest new therapy for drug-resistant cancerStaff Writer | May 11, 2018
A team of cancer researchers managed to exploit a vulnerability in melanoma that has developed resistance to a targeted therapy, providing a potential new therapeutic strategy to selectively kill the drug-resistant cancer cells.
Tumor A mutation in the BRAF gene
Rene Bernards of the Netherlands Cancer Institute and Oncode Institute and his team exposed 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.
Since more than half of all melanoma patients have a mutation in this BRAF gene, the BRAF-inhibitor stops tumor growth for those patients. But within a few months, the tumor cell adapts the original signaling pathway and becomes active again, and even hyperactive.
The researchers, however, found that the hyperactive resistant melanoma cells produced large amounts of reactive oxygen species, but cancer cells that were still sensitive to the drug did not do this.
Reactive oxygen species is a double-edged sword, according to the researchers. 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.
Bernards' team found that the abundance of free radicals caused the resistant melanoma cells to stop dividing, but they didn't die.
Then, they tested this on mice with an existing drug, vorinostat, which is known to stimulate the production of free oxygen radicals. In mouse models, the researchers saw tumors shrink under the influence of vorinostat.
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 tumor has become resistant, stop giving those inhibitors and immediately treat the patients with vorinostat to kill the resistant cancer cells.
"It is not a combination drug," said Bernards. "It is very important that you first stop the signalling pathway inhibitors because they suppress the free radicals and thus eliminate the effects of vorinostat." ■