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 may expand the number of possible new therapeutic targets for this disease.
In this new study, published online July 9, 2014, in the journal Nature, researchers from the Cancer Genome Atlas (TCGA) Research Network, led by Dana-Farber scientist Matthew Meyerson, MD, PhD, examined the genomes, RNA, and some 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 Meyerson, who is also a Broad senior associate member. “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, a post-doctoral fellow in the Meyerson lab and co-author 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.”
In the group’s initial scan of the tumor samples, researchers identified gene mutations that would increase RTK/RAS/RAF pathway activity in 62 percent of the samples. The affected genes are oncogenes, or genes that have the potential to cause cancer when mutated or expressed at high levels. Consequently, 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 (multiplication) 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 percent of patients with lung adenocarcinoma, a significant improvement from a decade ago,” said 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 co-author Joshua Campbell, a post-doctoral 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.”
In the aggregate, the several forms of lung cancer comprise the most common cause of cancer-related deaths worldwide, with more than 1 million deaths annually. The National Cancer Institute estimates that only 17.5 percent of people diagnosed with lung cancer are still alive five years later. Lung adenocarcinoma, the most common form in the United States, develops in tissues near the outer parts of the lungs and can spread widely. Although smoking is the main risk factor, adenocarcinoma is also the most common type of lung cancer among lifelong non-smokers, and the risk of lung cancer is increased by 20 to 30 percent by exposure to secondhand smoke.
This work was supported by the following NIH grants: U24 CA126561, U24 CA126551, U24 CA126554, U24 CA126543, U24 CA126546, U24 CA137153, U24 CA126563, U24 CA126544, U24 CA143845, U24 CA143858, U24 CA144025, U24 CA143882, U24 CA143866, U24 CA143867, U24 CA143848, U24 CA143840, U24 CA143835, U24 CA143799, U24 CA143883, U24 CA143843, U54 HG003067, U54 HG003079 and U54 HG003273.