Targeted cancer drugs—those that selectively kill cancer cells—have been a revelation in cancer treatment, giving years of healthy life to some lucky patients. But unfortunately, only a subset of patients responds to the various therapies, and even those who do respond eventually grow resistant.
Now scientists are starting to figure out how to make those drugs work more effectively in a larger number of patients, in part by better understanding the complex inner workings of the cancer cell. In two studies focusing on a promising class of drugs for lung cancer called EGFR tyrosine kinase inhibitors, researchers have pinpointed new drug targets that could enhance the drugs’ activity. They hope the findings will enable a new approach to personalized cancer care, suggesting specific combinations of drugs that will be most effective for an individual’s cancer.
“We have hundreds of drugs now in development and cannot test them in all possible combinations,” says Philip Sharp, Institute Professor at the Koch Institute for Integrative Cancer Research at MIT. “To personalize cancer care, we must interpret changes in cellular networks or mutations to predict the correct drug combination to use. [These] results indicate that this is beginning to become possible.”
EGFR inhibitors work in about 10 to 40 percent of lung cancer patients, depending on ethnicity, gender, and smoking history. People whose cancers have mutations in the gene for EGFR are also more likely to respond to the drugs, but these mutations aren’t as predictive as scientists had hoped. Not everyone who does well on the drug has the mutation—depending on the study, about 10 to 60 percent of responders don’t have it—and not everyone with the mutation responds.
Starting with a line of cancer cells known to be resistant to EGFR inhibitors, Charles Sawyers and collaborators at Sloan Kettering silenced a selection of cancer-related genes one by one. They found they could make the cells sensitive to the drug by inhibiting different genes in a molecular pathway called NF-Kappa Beta, which regulates cell division and death.
The findings held true in lung cancer patients; among patients with the EGFR mutation, those with higher activity in this pathway fared much worse when given the drug than those with lower activity. The results suggest that EGFR inhibitors would be more effective in some patients if given along with drugs that inhibit the NF-Kappa Beta pathway.