Targeting a Mean Mutation

K-Ras Ramalingam

By Quinn Eastman / Photography by Jack Kearse

Lung cancer trial suggests a strategy for targeting a mean mutation

The "divide and conquer" approach to cancer therapy has been increasingly prominent in recent years. This strategy identifies drugs that are particularly effective against tumors carrying certain growth-driving mutations.

Two recent examples include crizotinib, approved by the FDA for non-small-lung cancer with a translocation in the ALK gene, and vemurafenib, approved for melanomas with mutations in the B-raf gene.

One inevitable drawback: if someone's tumor doesn't carry the specified mutation, these drugs can't help. The mutation that makes a tumor vulnerable to crizotinib is found in only a small percentage of lung cancers.

So when designing a research program in lung cancer, why not go after the targets that cause the most disease?

That's the rationale behind Winship researchers' hunt for ways to attack the worst of the worst: lung cancers with mutations in K-Ras, a gene that has long been considered "undruggable."

Lung cancers with mutations in K-Ras, which make up around a quarter of all non-small cell lung cancers (NSCLC), are known to be resistant to both chemotherapy and newer drugs. In the 1980s, the K-Ras gene was one of the first oncogenes identified, by virtue of its presence in a virus that causes cancer in rats. Basic scientists have examined ways to inhibit the effects of mutated K-Ras in cancer cells, without much success.

Suresh Ramalingam, Winship's chief of thoracic oncology and director of medical oncology, says K-Ras and another frequently mutated gene in lung cancer, LKB-1, are at the center of Winship's strategy for lung cancer research. That strategy has been identified as a major focus for the Emory Lung Cancer NCI- funded program project grant entitled "Targeting Cell Signaling in Lung Cancer to Enhance Therapeutic Efficacy." Winship's deputy director, Fadlo R. Khuri, and Haian Fu, both of whom have devoted a number of years to identifying cancers with K-Ras mutations, lead that application, and targeting K-Ras is a major focus of a project in the grant co-led by Ramalingam and Yuhong Du.

"The significance of K-Ras mutations, as far as poor outcomes with chemotherapy with NSCLC, has been well known, " Ramalingam says. "The field has been looking for a way to target K-Ras for a long time. You can think of this as a big white elephant sitting in the room, demanding attention."

Now research led by Winship researchers has provided leads for two strategies that may help doctors capture this elusive target. Both involve anticancer agents that are already in clinical trials.

One of the leads involves "death receptors," molecules on cells that act as built-in self-destruct buttons and halt the progress of cells that could become cancerous. Finding a way to push these buttons on cancer cells has been an appealing goal, but clinical studies of antibodies that target death receptors have been disappointing so far.

In a paper published in Journal of Biological Chemistry, Winship researcher Shi-Yong Sun and colleagues have shown that antibodies that target death receptors are more effective against cells with mutations in K-Ras. The mutations cause the cells to put more death receptors on their surfaces, making the cells more vulnerable.

Another promising strategy involves observations from a recent trial led by Ramalingam. The study was testing a combination of erlotinib, an FDA-approved drug for non-small cell lung cancer, and an antibody against insulin-like growth factor receptor (IGF-1R), an experimental drug. Though the combination did not prove successful for the entire study population, the investigators discovered that those with K-Ras mutations seemed to do better.

"In this study, the presence of a K-Ras mutation was associated with a poor outcome with erlotinib alone but predicted a favorable outcome with the combination," Ramalingam says. "This suggests that future trials of this combination with IGF-1R targeted agents should focus on patients whose tumors carry the K-Ras mutation."

He adds that the emphasis on K-Ras is part of a larger effort to tailor lung cancer therapy to each patient's disease. Winship has been participating in research studies, such as the Lung Cancer Mutation Consortium, a 14-center National Cancer Institute-supported study where each patient's tumor DNA is checked for a panel of common mutations, including K-Ras. That information is then used to direct their treatment, either to known targeted therapies or to clinical trials of new therapies.

"Our eventual goal is to be able to offer every patient the best therapeutic options, as determined by genetic analysis of the tumor, whether they have a K-Ras mutation or not," Ramalingam says.

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