Cancers often become resistant to therapy, which is one of the major challenges in patient care. Sometimes however, cancers are not only resistant but also addicted to the very drugs that were supposed to eliminate them. Indeed, studies in patients, animal models and cultured cells have suggested that this dependency can be used against tumors: it turns out that drug-addicted cells massively die when treatment is suddenly stopped. Although this is a potential new avenue to fight cancer, it was not clear how best to exploit this vulnerability in the clinic, because the mechanism of addiction was unknown. Until now.
To reveal the mechanism of cancer drug addiction, it is probably best to try to break it, argued group leader Daniel Peeper and his postdoc Xiangjun Kong at the Netherlands Cancer Institute. They started off with melanoma cells that were both resistant and addicted to a treatment based on inhibition of BRAF, a common driver of malignancy. With a popular technique called CRISPR-Cas9 they knocked out all individual genes in the cancer cells' genome, one by one. Then, they searched for cells carrying a mutation that had broken the addiction. Those were the cells that had managed to survive when treatment was discontinued. All others died. With this strategy, the researchers identified a signaling pathway vital for drug addiction, involving the proteins ERK2, JUNB, and FRA1. Peeper: "Interestingly, all resistant tumor cells we examined used this same drug addiction mechanism irrespective of how they had become resistant."
"When this pathway is disrupted, cancer cells overcome their drug addiction", continues Peeper (see illustration). "We have demonstrated this in both cell culture and tumor-bearing mice, and we have indications of the same phenomenon in patients with drug-resistant melanoma. 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."