The scientists chose to study L858R because, unlike other mutations that affect EGFR, it has a unique impact on EGFR function. “Unlike all other mutations, this mutation requires that receptors pair up in the cancer cell membrane, after which, signals instructing the cell to start replicating are sent to the nucleus,” Yarden explains. “Using a mouse model of lung cancer with the L858R mutation, we discovered that, if this pairing does not occur, it’s like a short-circuit – the signal to initiate cellular replication cannot be sent to the nucleus, and the tumor does not grow.”
The researchers then blocked the pairing by treating the mice with an antibody drug called cetuximab, known by its trade name Erbitux, developed on the basis of research by Yarden and the late Prof. Michael Sela. Erbitux has been approved by the FDA for the treatment of colon and head and neck cancers.
“After the treatment with Erbitux, the lung tumors of mice shrank and did not reappear, not even after a long while,” Yarden says. “These results indicate that, for the large number of human lung cancer patients who have the L858R mutation, a single drug might offer a path toward full recovery, without the devastating phenomenon of cancer relapse.”
The new study also explains why previous attempts to treat EGFR-mutated lung cancer with Erbitux had failed or, at best, produced conflicting results. Explains Yarden: “Since new EGFR inhibitors were approved as lung cancer drugs nearly 10 years ago, all patients now receive these anti-EGFR medications, irrespective of the identity and number of their EGFR mutations. They are highly effective for a while, but they permit the emergence of secondary mutations that accelerate cancer relapse. By the time Erbitux is given, it is usually ineffective because it can work only against certain EGFR mutations. Our study demonstrates the importance of preselecting lung cancer patients who can be effectively treated with Erbitux from the start, based on their mutation profile.”