Setback to personalized cancer treatment

A new study suggests that tumour cells may develop resistance to potential Ras inhibitors – currently one of the most studied cancer treatments.

Mutations in Ras are those that initiate many of the most lethal tumours, and the search for pharmaceuticals that inhibit these proteins has become a priority in the battle against cancer. However, the results of this treatment may be far less positive than speculated according to a study published in the Genes & Development journal by the Genomic Instability Group at the Spanish National Cancer Research Centre (CNIO).

Research leader Óscar Fernández-Capetillo: “The message is not good, but the knowledge is important for cancer research and the so frequently mentioned personalised medicine.”

Discovered in 1982, alterations in Ras genes were the first mutation described in cancer. This was a paradigm-shifting discovery and for the first time revealed that tumours are initiated by mutations in our own genes. It raised the hope that inhibitors for these mutated genes could tackle cancer. “It is the base of personalised medicine,” explained Fernández-Capetillo.

The study also found that certain tumour cells were capable of growing even in the absence of serum, if the gene Erf was also eliminated. Fernández-Capetillo said: “For me, this discovery was the origin of the project as it made us speculate that if cells can grow with hardly any nutrients upon eliminating ERF, this could even allow the growth of RAS-free cells”. This hypothesis turned out to be true: eliminating ERF allows mouse embryonic stem cells to grow, differentiate and even generate tumours in total absence of Ras genes. ERF is in essence a form of brake that limits the consequences of Ras activation.

As a result, tumours may be capable of becoming resistant to Ras treatment by accumulating mutations in genes like ERF. Recent studies have found ERF mutations in cancer patients, indicating that such situation may indeed exist in the clinic. Therefore, Fernández-Capetillo’s group is now exploring whether mutations in ERF can account for the resistance to personalised therapies against inhibitors of the RAS route.