Thoracic surgeon and lung cancer specialist David Jones says discovery of the mutation and its effects could lead to therapies that would benefit many people with lung cancer.
-
An inherited mutation in a gene called BRMS1 promotes lung cancer metastasis.
- The mutation could be targeted with therapies that prevent metastasis.
Lung cancer is the leading cause of cancer death in the United States. The primary reason the disease is so deadly is that it often spreads (or metastasizes) — even when detected early. Now the laboratory of Memorial Sloan Kettering Cancer Center (MSK) surgeon-scientist and lung cancer specialist David Jones has discovered an inherited mutation that promotes lung cancer metastasis.
Dr. Jones discusses how his lab identified the mutation and how this discovery may lead to therapies that block lung cancer metastasis in patients with the mutation.
What did you learn about lung cancer metastasis from this study?
About half of people with earlier-stage lung cancer develop metastases within a few years. There is a misconception that early-stage tumors that are surgically removed will not return, including when patients receive chemotherapy following surgery. Unfortunately, that’s not true. My laboratory research focuses on understanding why this happens. Specifically, what are the risk factors that make a person more prone to develop metastases following complete surgical removal of lung cancer?
We now have identified an inherited mutation (also called a germline mutation) in a gene called BRMS1 that we believe enables the lung cancer to spread. We also have clarified how the mutation leads to metastasis and tested a therapeutic strategy that could prevent the development of metastases. We reported this finding on October 5, 2022, in Science Translational Medicine.
How did you identify the BRMS1 mutation leading to lung cancer metastasis?
We focused on a group of genes known as metastasis suppressor genes. These genes make proteins that stop cancer from spreading. We have been especially interested in BRMS1, which stands for breast cancer metastasis suppressor 1. We hypothesized that a mutation in BRMS1 causes the protein it makes to fail in its normal role of inhibiting metastases, with the result being a spread of the lung cancer.
We analyzed BRMS1 gene-sequencing data from people with lung cancer. We then examined the gene for specific types of mutations called single nucleotide polymorphisms, or SNPs (pronounced “snips”). These genetic variations frequently involve a change in only one of the four “letters” of the DNA code. SNPs are germline mutations, meaning they are inherited and present in all cells, not just the cancer cells.
Our analysis revealed a SNP called rs1052566, which was associated with an increased risk of metastasis in several large lung cancer databases. We showed that a person who has the rs1052566 SNP and develops lung cancer is at higher risk of having the cancer spread, even following curative surgery.
Importantly, there is no evidence that people with this mutation are at higher risk for developing lung cancer, only that this BRMS1 mutation makes it more likely to spread once you have lung cancer.
How common is the rs1052566 SNP in the BRMS1 gene?
In some populations, it is fairly common. In South Asians, about 28% of people carry this germline mutation, while it is found in 8% of people from European descent.
How did you reveal the mechanism by which the SNP causes metastasis?
We studied human lung cancer cells with the SNP in the laboratory and in patient-derived organoids — miniaturized versions of lung tumors that behave like patients’ original tumors. We discovered that not only did the germline alteration suppress the function of the BRMS1 protein, but it also activated a cancer-promoting pathway called c-fos.
The SNP had a dual effect, like taking off the brakes and pushing the accelerator at the same time. Our studies suggested that blocking the c-fos pathway could slow or even prevent the development of metastasis.
What experiments did you do to see if the c-fos pathway could be blocked?
We began to look at specific agents that block the c-fos pathway and realized clinical trials had already been done testing an investigational drug in people with a type of spinal deterioration and people with rheumatoid arthritis. We repurposed this drug (called T5224) and tested it in our mouse and human lung cancer organoid models for lung cancer that carried the BRMS1 SNP. There was a dramatic reduction in the development of metastases in all models, confirming that this germline mutation could be targeted by therapies.
How could this finding improve treatment of lung cancer metastasis?
A drug that blocks metastasis in a significant percentage of people could benefit many lung cancer patients. We currently use targeted therapies directed toward specific cancer gene mutations that occur in only 2% to 3% of the population, so our observations about BRMS1 and its impact on more individuals is compelling.
What is the next step in advancing this to being tested in people with lung cancer?
We hope to work with the Marie-Josée and Henry R. Kravis Center for Molecular Oncology about adding the rs1052566 SNP to MSK-IMPACT®, the tumor-sequencing test available to MSK patients. MSK-IMPACT® already analyzes more than 500 genes that play a critical role in the development and behavior of tumors. Identification of this newly discovered germline BRMS1 SNP could then be integrated into new clinical trials.
At MSK, we would expect the BRMS1 SNP to appear in about 8% of patients, given our patient demographics. For people with lung cancer who have this germline alteration, we could offer a clinical trial testing T5224 or another c-fos inhibitor to assess its ability to prevent metastases.
What is special about the clinical and laboratory resources at MSK that makes a finding like this possible?
Lung cancer research at MSK is made possible by a collaborative approach that tackles the important issue of why patients die from lung cancer — which is primarily due to the metastases. Our knowledge about the genetic basis of all cancer, particularly lung cancer, establishes a strong foundation for our lab and others to leverage both tumor and patient gene-sequencing data to identify new therapies for this deadly disease.
