A research team from the Netherlands Cancer Institute has discovered the underlying mechanism of cancer drug addiction that can lead to the development of more rational alternating therapies to kill cancer cells.
Often, cancer cells not only become resistant to existing therapy but also become addicted to the treatments that are supposed to combat and eliminate them.
Studies in patients, animal models and cultured cells have shown that the dependency can be used against tumours, where the drug-addicted cancer cells die in large numbers when the treatment is suddenly discontinued.
Led by Netherlands Cancer Institute professor Daniel Peeper, the research was initially carried out with melanoma cells that were both resistant and addicted to a therapy based on inhibition of BRAF, which is a common driver of malignancy.
The study team used the CRISPR-Cas9 technique to kill all individual genes, one by one, in the cancer cells’ genome.
Following this, the scientists searched for cells carrying a mutation that had broken the addiction.
These cancer cells were the ones that managed to survive when the treatment was stopped, while all the remaining cells were killed.
Using the method, the researchers recognised a signalling pathway vital for drug addiction, involving proteins ERK2, JUNB, and FRA1.
Additionally, the team not only halted the treatment but subsequently treated the cancer cells with the chemotherapeutic dacarbazine.
The combination of sudden drug discontinuation and a different second treatment option proved to be more effective than only withdrawing the treatment.
The new findings can be used to target the addicted cancer cells that survived even after stopping the first treatment option.
Peeper said: “Instead of giving addicted cells a break we should probably immediately switch to another treatment.
“Now that we understand how cancer cells can overcome their drug addiction, we have a solid basis for identifying the most effective second treatment for this so-called alternating therapy approach.”
Peeper further added: “This was a proof-of-principle experiment in cultured cells demonstrating how effective these alternating treatments may be.
“It sets the stage for systematic studies identifying which treatments cooperate best with drug withdrawal for therapy-addicted cancers.”
The research received financial support from the Dutch Cancer Society and the European Research Council.