Most lung cancer patients are smokers or have kicked the habit. There are also nonsmokers who develop lung cancer as well, and they can be treated effectively with new drugs on the market.
But these medications tend to lose effectiveness as time goes on because the malignancies develop secondary mutations in a gene called EGFR (epidermal growth factor receptor) that the drugs usually don’t overcome.
A mutation in the gene for EGFR results in a protein on cells that helps them grow and then cause cancer. In new research published in the journal Cell Reports Medicine, scientists at the Weizmann Institute of Science in Rehovot found a way that could lead to relapse-free treatment for a sizeable subgroup of lung cancer patients.
In the mouse model study, they discovered a biomarker that could help doctors select lung cancer patients for treatment with a single antibody-based drug that, it is hoped, will bring about a full remission without a relapse of cancer.
“We have found a potential biomarker that may change the way patients with lung cancer are treated worldwide.”
– Prof. Yosef Yarden
“Similar to how the presence of BRCA mutations predicts how breast and ovarian cancer patients will respond to drugs, the new biomarker could make it possible to match some lung cancer patients with the specific medication most likely to help them,” said Prof. Yosef Yarden of Weizmann’s immunology and regenerative biology department who led the study.
Results of the study
The current research began when Dr. Ilaria Marrocco – then a postdoctoral researcher in Yarden’s lab – reviewed the results of 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 located in their individual tumors.
These patients eventually developed drug resistance that led to a 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.
“Dr. Marrocco’s observation inspired us to search for a biomarker that would predict which patients would respond well to therapy, according to the specific mutations they carry,” recalled Yarden.
The scientists decided to focus on one of the two most common gene variants associated with EGFR in lung cancer: the L858R mutation, in which a single amino acid, out of several hundred, is replaced with another one, at point 858 in EGFR. This mutation occurs in about 40% of lung cancer patients whose tumors are characterized by EGFR mutations.
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 explained.
“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 which was developed on the basis of research by Yarden and the late Prof. Michael Sela. Erbitux has already been approved by the US Food and Drug Administration (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 noted. “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. “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,” Yarden said.
“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 shows the importance of preselecting lung cancer patients who can be treated effectively with Erbitux from the beginning based on their mutation profile.”
The next challenge will be to launch a clinical trial to study the effectiveness of this treatment for people with lung cancer, which could be speeded up by the fact that Erbitux has already been approved for treating other types of cancer. In the meantime, Yarden and Marrocco are excited about the potential for their research to eventually have an impact on clinical practice.
“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,” concluded Marrocco, the paper’s lead author who is now a researcher in the department of life sciences and public health at the Università Cattolica del Sacro Cuore, in Rome.
