Results of a study by scientists at Johns Hopkins which was funded by the National Cancer Institute, identify a molecular marker called mitogen-inducible gene 6 or Mig6, a negative regulator of EGFR through the upregulation of the PI3K-AKT pathway. This molecular marker appears to accurately predict longer survival among patients prescribed two of the most widely used drugs in a class of anticancer agents called EGFR-inhibitors. These preliminary results need further confirmation.
The U.S. Food and Drug Administration-approved drugs, gefitinib (Iressa?, AstraZeneca) and erlotinib (Tarceva?, Genentech/Astellas Oncology), are prescribed for patients with lung cancer and pancreatic cancer. But only a few patients who have mutations in the EGFR-gene usually benefit with a prolonged reduction of tumor size. The two drugs block the gene’s ramped-up protein production, but patients’ response to the drug varies widely ? from no survival benefit to several years. The average is several months. This limited sensitivity to anti-epidermal growth factor receptor EGFR tyrosine kinase inhibitors (TKIs) can be explained by the presence of EGFR tyrosine kinase (TK) domain mutations.
Low levels of Mig6 help us to predict clinical benefit…
Response to EGFR
“Clinicians have had no reliable method for distinguishing patients who are not likely to respond to EGFR inhibitors and those who will respond very well,” says David Sidransky, M.D., professor of otolaryngology, oncology, pathology, urology, and genetics at Johns Hopkins. “Looking at the precise level of protein production from the EGFR-gene alone in specific patients has not proven to be a good indicator of patients’ response to EGFR-blocking drugs, but the presence or absence of Mig6 might be,” he notes.
In a preliminary study, published in the July 31, 2013 edition of the online journal, PLoS ONE, the Johns Hopkins scientists found the genetic marker in a series of experiments that began with laboratory-derived lung and head and neck cancer cell lines resistant to EGFR-inhibitor drugs. In the cell lines, the team found very high levels of protein production from the Mig6-gene, up to three times the level in sensitive cell lines. Mig6 is one of the molecules that controls the activity of the EGFR-protein.
“In the first set of experiments, we found that higher levels of Mig6 occur often in cells that don’t respond to EGFR inhibitors,” Sidransky explains. “Most tumors are known to have high Mig6-levels and are not expected to respond to EGFR-inhibitors.”
Next, the research team studied Mig6-levels in a variety of tumors that were directly engrafted into mice, a research model known as a xenograft, and treated with an EGFR-inhibitor. These new models contain a more complete sampling of the tumor that includes stromal cells, which surround and interact with the cancer cells. “These tumors are implanted along with their own microenvironment, into the mice, and we believe this model may be more predictive of what happens in human patients,” Sidransky says.
In the xenografts of tumors without EGFR-mutations, as Mig6-levels increased, so did the resistance to EGFR-inhibitors, suggesting a correlation between high Mig6 and lack of response to the drugs. To confirm the correlation, the scientists tested tissue samples of 65 lung cancer patients treated with EGFR-inhibitors to compare their Mig6-levels with outcomes.
The researchers found that EGFR activity, which was more accurately predicted by the ratio of Mig6/EGFR, highly correlated with erlotinib sensitivity in panels of cancer cell lines of different tissue origins.
Analyzing the results, the researchers showed that of 18 patients with low Mig6-levels, five survived more than a year without progression of their cancer. Furthermore, four patients survived more than two years progression-free. Among 16 patients with higher Mig6-levels, two survived more than one year and none survived, progression-free, beyond two years.
“The beauty of this finding is that it’s simple. We’re looking for tumors with low levels of Mig6 to predict clinical benefit, and there aren’t many of them,” expained Sidransky.
Sidransky’s team expects to license the Mig6-marker to a biotechnology or pharmaceutical company and conduct further tests in larger groups of patients.
For more information:
Chang X, Izumchenko E, Solis LM, Kim MS, Chatterjee A, Ling S, Monitto CL, et al. The Relative Expression of Mig6 and EGFR Is Associated with Resistance to EGFR Kinase Inhibitors. PLoS One. 2013 Jul 31;8(7):e68966. doi: 10.1371/journal.pone.0068966. Print 2013.[Article][PubMed]
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