The most common genetic subtype of lung cancer, which has long defied treatment with targeted therapies, has had its growth halted by a combination of two drugs already in use in laboratory and animal studies, setting the stage for clinical trials of these drugs in patients.
The study, published in Cancer Discovery (2014; doi:10.1158/2159-8290.CD-13-0646), describes a new tack in the treatment of lung adenocarcinomas that carry mutations in the gene KRAS, which account for about 40% of all lung cancers. While most efforts to target KRAS directly with drugs have not proven successful, the authors of the current study took a more circuitous approach—targeting KRAS‘s accomplices, the genes that carry out its instructions, rather than KRAS itself.
“About 30% of lung adenocarcinomas have mutations in KRAS, which amounts to nearly 30,000 of all patients diagnosed with lung cancer each year in the United States,” said the study’s senior author, David Barbie, MD, of the Lowe Center for Thoracic Oncology at Dana-Farber and the Broad Institute of Harvard and the Massachusetts Institute of Technology in Boston. “That represents the single biggest subset of lung cancer patients, if grouped by the mutations within their tumor cells. Unfortunately, there hasn’t been a reliable way at striking at the genetic mechanism that causes these cells to proliferate.”
Mutations in KRAS cause cancer cells to grow and divide in a wildly disordered way. The lack of drugs able to block KRAS safely has led investigators to look for ways of stifling its effects downstream—by interfering with the signals it sends to other genes.
Barbie was studying one of these signaling pathways, which involves TBK1, a protein active in the immune system. He conducted a search of scientific literature to see if there are any compounds capable of blocking this protein. One study stated, deep in the footnotes, that a drug known as CYT387—already being tested as a treatment for the bone marrow disorder myelofibrosis—is also active against the TBK1 protein.
The researchers tested CYT387 in laboratory samples of lung adenocarcinoma cells and found it to be a potent inhibitor of TBK1 and, as a bonus, an effective suppressor of cytokines, proteins that congregate in the tissue around tumors and help cancer cells survive and spread to other parts of the body. Animal studies produced similarly encouraging results.
The research team next ran tests in more aggressive lung adenocarcinomas, which, in addition to having mutations in KRAS, also had mutations in the key gene p53. When they tested two drugs in tandem—CYT387 and AZD6244—they found that the combination was potent against the tumors, both in laboratory cell samples and in animals with the disease.
They explained that their next step is to test these results in lung cancer patients. They are in the process of developing a clinical trial, and these findings may also be tested in colon and pancreatic cancer, which share these mutations.