Breaking the back of cancer cell drug addiction — pathway identified in new research

A research team from the Netherlands Cancer Institute has discovered the underlying mechanism to why cancer cells become addicted to the drugs that are administered to kill them, which may lead to more rational alternating therapies.

Published in a letter in the journal Nature, this research started with the team trying to break the cancer cells drug addiction. To do this they took melanoma cells that were both resistant and addicted to a treatment based on inhibition of BRAF and then ‘knocked out’ all the individual genes in the cancer cells’ genome using CRISPR-Cas9. The team then searched for cells that had survived once treatment was discontinued, which were carrying a mutation that had broken the addiction.

Through this strategy, it was possible for the researchers to identify the signalling pathway involved in cancer cell drug addiction. “Interestingly, all resistant tumour cells we examined used this same drug addiction mechanism irrespective of how they had become resistant,” said research team leader, professor Daniel Peeper.

“When this pathway is disrupted, cancer cells overcome their drug addiction. We have demonstrated this in both cell culture and tumour-bearing mice, and we have indications of the same phenomenon in patients with drug-resistant melanoma,” he added. “This mechanism was active also in lung cancer cells that were addicted to another drug. This suggests that the pathway we uncovered may be important for various cancer types and treatments.”

As cancer cells are flexible it is possible for them to reverse their addiction themselves, so, these findings may be used to target those cells that do not die once treatment is stopped. “Instead of giving addicted cells a break we should probably immediately switch to another treatment,” Peeper continued. “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 and his team tested out this immediate treatment switching technique and found that when they stopped BRAF-inhibitor treatment and then immediately started chemotherapeutic dacarbazine treatment, they achieved better results than with treatment cessation alone.

“This was a proof-of-principle experiment in cultured cells demonstrating how effective these alternating treatments may be,” Peeper summarised. “It sets the stage for systematic studies identifying which treatments cooperate best with drug withdrawal for therapy-addicted cancers.”