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Researchers from Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, and other centers have identified novel mutations in a well-known cancer-causing pathway in lung adenocarcinoma, the most common subtype of lung cancer. Knowledge of these mutations could potentially identify a greater number of patients with treatable mutations because many potent cancer drugs that target these mutations already exist. In addition, these findings, published online in Naturemay expand the number of possible new therapeutic targets for this disease.
Study Details
In this new study researchers from the Cancer Genome Atlas (TCGA) Research Network, led by Dana-Farber scientist Matthew Meyerson, MD, PhD, examined the genomes, RNA, and protein from 230 lung adenocarcinoma samples. In three-quarters of the samples, the scientists ultimately identified mutations that put a cell-signaling pathway known as the RTK/RAS/RAF pathway into overdrive.
“Lung adenocarcinoma is the leading cause of human cancer death. This is because there are so many ways to develop the disease, and many different pathways are altered in this cancer,” said Dr. Meyerson. “In recent years, we have made enormous progress in lung adenocarcinoma treatment by targeting EGFR, ALK, and other mutated proteins. Through this study, we are able to add to the range of such alterations and therefore gain potential new therapeutic targets.”
Mutations affecting the RTK/RAS/RAF pathway can cause it to become stuck in the “on” state. As a result, signals that promote cancer cell proliferation and survival are produced continuously. However, drugs are currently available that curb aberrant activity of this pathway and prompt therapeutic responses in patients.
“About 10% of patients have tumors with EGFR mutations, and these patients uniquely benefit from anti-EGFR therapy,” said Alice Berger, PhD, a postdoctoral fellow in the Meyerson lab and coauthor of the study. “We were motivated to find genetic aberrations in patients that lack EGFR mutations and that might be similarly suitable for therapeutic targeting. Ultimately, we want to be able to provide every patient with an effective drug for their specific cancer.”
Oncogene Mutations Identified
In the group’s initial scan of the tumor samples, researchers identified oncogene mutations that would increase RTK/RAS/RAF pathway activity in 62% of the samples; these tumor samples were classified as oncogene-positive. To identify additional alterations, the investigators looked at DNA copy number changes, or changes in gene number resulting from the deletion or amplification of sections of DNA in the genome. In doing so, they detected amplification of two oncogenes, ERBB2 and MET, which are part of the RTK/RAS/RAF pathway in the oncogene-negative cancers. Gene amplification usually leads to increased expression of the encoded protein in cells.
Now that these amplifications have been identified in cancers without other activity of the RTK/RAS/RAF pathway, clinicians may be able to treat patients whose tumors have specific gene changes with drugs that are either currently available or under development.
“It is quite striking that we have now identified an actionable mutation in over 75% of patients with lung adenocarcinoma, a significant improvement from a decade ago,” said Dr. Meyerson.
Additional analysis identified other genes that may play important roles in lung cancer development. Mutations in one of these genes, NF1—a known tumor suppressor gene that regulates the RTK/RAS/RAF pathway—had previously been reported in lung cancer. Mutations of NF1 also put that pathway into overdrive. Another mutated gene, RIT1, is also part of the RTK/RAS/RAF pathway, and this is the first study to associate mutation of this gene with lung cancer.
“This is one of the most comprehensive studies of lung adenocarcinoma to date,” said coauthorJoshua Campbell, PhD, a postdoctoral fellow in the Meyerson lab. “The TCGA data enabled us to profile and analyze DNA, RNA, and methylation from over 200 tumors, and it made the discovery of these rare alterations possible.”


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