April 18, 2011 (Orlando, Florida) — The discovery of mutations in the DDR2 gene might help lead to more effective treatments for squamous cell lung cancer. According to new data, DDR2 mutations are present in about 4% of lung squamous cell cancers, and are associated with sensitivity to the tyrosine kinase inhibitor dasatinib (Sprycel).
The study results were published online April 3 in Cancer Discovery, the newest journal of the American Association for Cancer Research (AACR), which was launched here at the AACR 102nd Annual Meeting. The study findings were highlighted at a press briefing.
Nonsmall-cell lung cancer accounts for 85% of all cases of the disease, and patients who respond to epidermal growth-factor receptor (EGFR) kinase inhibitors generally have the adenocarcinoma subtype of the disease. "We've made major advances in the treatment of lung adenocarcinoma with the development of genomically targeted therapies," said lead researcher Matthew Meyerson, MD, PhD, professor of pathology at the Dana-Farber Cancer Institute in Boston, Massachusetts.
Several promising therapeutic targets have been identified — including EML4-ALK, KRAS, and MET — and experimental agents directed against these targets are being studied in clinical trials, he noted. However, these targets appear to be largely limited to adenocarcinomas.
"There are very few known targets for the treatment of squamous cell lung cancer, however, and no approved targeted therapies," he explained during the press briefing.
In this study, Dr. Meyerson and colleagues attempted to identify new therapeutic targets by analyzing the tyrosine kinome of squamous cell cancer of the lung for possible kinase mutations.
DDR2, which is a receptor tyrosine kinase that binds collagen as its endogenous ligand, has been previously reported to promote cell migration, proliferation, and survival. This occurs when it is activated by ligand binding and phosphorylation, note the researchers.
Sensitivity to Dasatinib
The researchers conducted a systematic screening in which all protein tyrosine kinase genes were analyzed for somatic mutations in 290 specimens of squamous cell cancer. "We found mutations in several kinase genes, including the DDR2 gene, and mutations were found in 11 of the 290 squamous cell cases, for a total of 3% to 4%," said Dr. Meyerson.
"Then we asked if there were any existing protein kinase inhibitors that could inhibit the growth of squamous cell lung cancers harboring DDR2 mutations," he added.
The researchers identified 2 cell lines of squamous cell lung cancer that harbored DDR2 mutations. Of all the drugs they tested, they found dasatinib to be the most potent in preventing the growth of these cell lines.
When tested in animal xenograft models, tumors from a DDR2 mutant cell line were found to be sensitive to dasatinib.
In addition, a patient with squamous cell lung cancer exhibited a radiographic response to combination treatment with dasatinib and erlotinib. The patient did not harbor an EGFR mutation, Dr. Meyerson pointed out, but was subsequently found to have a DDR2 kinase domain mutation.
These data might have an important implication for the treatment of squamous cell lung cancer, he concluded. "The role of DDR2 as the causation of squamous cell lung cancer needs to be further validated," he said.
Because "dasatinib is already approved for clinical use, it is worth exploring clinical trails of dasatinib for squamous cell lung cancer," he added. "Diagnosis should include an analysis of candidate drug targets, including EGFR and DDR2."
It is unfortunate that most of the most driver mutations that have been identified so far are in adenocarcinoma, as opposed to the other subtypes of nonsmall-cell carcinoma, explained William Pao, MD, PhD, associate professor of medicine and director of personalized cancer medicine at Vanderbilt University, Nashville, Tennessee.
"Squamous cell carcinoma has been considered to be the 'odd man out,' not only because we haven't found a lot of targets there, but because a lot of the therapies we have now exclude patients with this subtype," said Dr. Pao, who served as a discussant of the paper.
Dr. Pao pointed out that he was excited by the study for this reason, and that the data "added to the growing list of targets that are being identified in squamous cell carcinoma."
The DDR2 gene "looks very promising as a target," he said. "Notably, we already have drugs available to target this specific mutation, so hopefully, we can develop some specific therapies for squamous cell carcinoma."
The study was supported by grants, awarded to individual researchers involved in the study, from the American Lung Association, United Against Lung Cancer, the Sara Thomas Monopoli Fund, the Seaman Corporation Fund for Lung Cancer, Genentech, the Department of Defense Lung Cancer Research Fellowship, Programme National d'Excellence/Institut National du Cancer, the German Ministry of Science and Education, the Max Planck Society, and the Deutsche Forschungsgemeinschaft. Dr. Meyerson reports being a consultant for Novartis; receiving research support from Novartis and Genentech; and being a consultant and an equity holder in Foundation Medicine and a patent holder for EGFR mutation testing licensed to Genzyme Genetics. Several coauthors have reported financial relationships with pharmaceutical/biotech companies, as indicated in the paper.
Cancer Discovery. Published online April 3, 2011. Full text
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