Nonsmokers who develop lung cancer can be treated effectively with new drugs, but their tumors refuse to surrender without a fight.
The drugs stop working in the long term because the tumors acquire secondary mutations that allow them to evade the medications’ therapeutic effect.
In research published in the journal Cell Reports Medicine, investigators from the Weizmann Institute of Science report findings that may lead to relapse-free treatment for a sizeable subgroup of lung cancer patients.
In a study in mice, the scientists have identified a biomarker that may help physicians select lung cancer patients who can be treated with a single antibody-based drug that is likely to bring about full remission, without cancer relapse.
“We have found a potential biomarker that may change the way patients with lung cancer are treated worldwide,” says Prof. Yosef Yarden of Weizmann’s Immunology and Regenerative Biology Department, who led the study. “Similar to how the presence of BRCA mutations predicts how breast and ovarian cancer patients will respond to drugs, the new biomarker might make it possible to match some lung cancer patients with the specific medication most likely to help them.”
Focusing on the mutations that matter
Most lung cancers are due to tobacco smoking, but the second-largest fraction of cases affects nonsmokers, and it’s characterized by mutations in a gene called EGFR. The current research began when Dr. Ilaria Marrocco, then a postdoctoral researcher in Yarden’s lab, reviewed the literature from clinical trials and realized that all patients with EGFR-positive lung cancer were being treated using the same multidrug protocol – regardless of which of the 30 known EGFR mutations were harbored in their individual tumors. These patients eventually developed drug resistance that led to cancer relapse. Marrocco wondered whether, by sorting lung tumors according to specific EGFR mutations, it might be possible to create a more personalized drug protocol and achieve better results.
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.”
The scientists say that the next step would be to launch a clinical trial to establish the effectiveness of this treatment for human lung cancer patients, something that will be made easier by the fact that Erbitux has already been approved for treating other cancer types. In the meantime, Yarden and Marrocco are excited about the potential for their research to eventually have an impact on clinical practice. Marrocco: “The L858R biomarker could help save lives by offering physicians a way to provide personalized drug treatment for lung cancer patients who carry the relevant mutation.”