Study Reports Success in Targeted Therapy for Lung Adenocarcinoma
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 already-in-use drugs in laboratory and animal studies, setting the stage for clinical trials of the drugs in patients. The study, published in Cancer Discovery, describes a new strategy in the treatment of lung adenocarcinomas with KRAS mutations. While most efforts to target KRAS directly have proven unsuccessful, the authors of the current study took a more circuitous approach, targeting 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 senior author David Barbie, MD, of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute and the Broad Institute of Harvard and MIT. “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 of striking at the genetic mechanism that causes these cells to proliferate.”
Study Details
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.
Dr. 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 and found that the drug CYT387, which is already being tested as a treatment for myelofibrosis, is also active against the TBK1 protein.
Dr. Barbie and his colleagues tested CYT387 in laboratory samples of lung adenocarcinoma cells and found it to be a potent inhibitor of TBK1 and an effective suppressor of cytokines, which help cancer cells survive and spread to other parts of the body. Animal studies produced similarly encouraging results.
Combination Shuts Down Cytokine Signaling
The investigators next ran tests in more aggressive lung adenocarcinomas, which, in addition to having mutations in KRAS, also had mutations in the key gene TP53. They tested two drugs in tandem against these tumor samples: CYT387 and AZD6244, which inhibits MEK, another downstream protein of KRAS. Neither drug had much of an effect by itself, but together, they formed a potent combination against the tumors, both in lab and animal models.
“Cytokines play a key role in tumor survival and spread in cells with KRAS mutations,” Dr. Barbie stated, “so blocking cytokine signaling can deprive cancer cells of a critical survival strategy. Because the combination of a TBK1 and MEK inhibitor targets two pathways at once, it shuts off cytokine signaling very quickly.” The shutdown of cytokines contrasts with the effects of many other forms of targeted therapy, which impede cancer cells’ ability to proliferate.
The drug combination didn’t produce any notable side effects in the animal models,” Dr. Barbie noted. He added, however, that after about 8 weeks of treatment, the cancer cells became resistant to the regimen, highlighting the potential need for additional drug combinations to produce lasting remissions.
“The next step will be to take these results to the clinic, where the combination can be tested in lung cancer patients,” said co–senior investigator Kwok-Kin Wong, MD, PhD, of the Lowe Center for Thoracic Oncology at Dana-Farber. “We’re in the process of developing a clinical trial. Because KRAS mutations are also common in colon and pancreatic cancer, we’re hopeful that trials will be organized for these patients as well.”
William C. Hahn, MD, PhD, of Dana-Farber Cancer Institute, is the corresponding author for the Cancer Discovery article.
The study was funded by the National Institutes of Health, the V Foundation, the GTM Fund for Lung Cancer Research, the Friends of Dana-Farber Cancer Institute, and Uniting Against Lung Cancer.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
