of triple-negative cells, while simultaneous administration killed about 20 percent. About 2,000 genes were affected by pretreatment with erlotinib, the researchers found, resulting in the shutdown of pathways involved in uncontrolled growth.
“Instead of looking like this classic triple-negative type of tumor, which is very aggressive and fast-growing and metastatic, they lose their tumorigenic quality and become a different type of tumor that is actually quite unaggressive, and very easy to kill,” Lee says.
However, if the drugs were given in the reverse order, doxorubicin became less effective than if given alone.
This treatment worked not only in cancer cells grown in a lab dish, but also in mice with tumors. When treated with a one-two punch of erlotinib and doxorubicin, the tumors shrank and did not grow back for the duration of the experiment (two weeks). With chemotherapy alone, or when the two drugs were given at the same time, the tumors initially shrank but then grew back.
A combination of high-throughput measurements and computer modeling was used to reveal the mechanism for increased tumor killing, and to identify a biomarker for drug response. The researchers found that the treatment was most effective in a subset of triple-negative breast cancer cells with the highest levels of EGF receptor activity. This should allow doctors to screen patients’ tumors to determine which would be most likely to respond to this novel treatment.
The research is “groundbreaking in its demonstration that the principles of order and time are essential to the development of effective therapies against complex diseases,” Rune Linding, research group leader at the Technical University of Denmark, and Janine Erler, associate professor at the University of Copenhagen, wrote in a commentary accompanying the paper in Cell. “As disease researchers, we must consider network states, and this and other studies serve as a model for a new generation of cancer biologists.”
The concept of staggering drug treatments to maximize impact could be very broadly applicable, Yaffe says. The researchers found similar boosts in tumor killing by pretreating HER2-positive breast cancer cells with a HER2 inhibitor, followed by a DNA-damaging drug. They also saw good results with erlotinib and doxorubicin in some types of lung cancer.
“The drugs are going to be different for each cancer case, but the concept that time-staggered inhibition will be a strong determinant of efficacy has been universally true. It’s just a matter of finding the right combinations,” Lee says.
The findings also highlight the importance of systems biology in studying cancer, Yaffe says. “Our findings illustrate how systems engineering approaches to cell signaling can have large potential impact on disease treatment,” he says.
The research was funded by the National Institutes of Health Integrative Cancer Biology Program and the Department of Defense.
Image: Neil Ganem, Michael Yaffe and David Pellman