April 30, 2002
La Jolla, CA – A team led by Salk scientists has identified the probable link between the breast cancer drug Herceptin and cardiac failure, one of its common side effects. The results may also explain why a common combination drug regimen including Herceptin is particularly toxic.
Herceptin targets the protein Her 2 (for human epidermal growth factor receptor 2), which is over abundant in some breast cancer cells. The new study shows that the mouse version of Her 2, called erbB2 (for erythrocyte blastosis virus B2) is needed for proper heart cell function.
“It was possible that Herceptin triggered cardiac malfunction by a number of mechanisms, but now it appears to be that the drug’s direct action on erbB2 is the culprit,” said Kuo-Fen Lee, a Salk associate professor and senior author of the study appearing in today’s Nature Medicine.
Lee added it should be possible to engineer new generations of drugs that would ameliorate Herceptin’s deleterious effects on heart function.
“To do that we need to know more about the role of erbB2 in both cancer and heart cells,” he said.
In the study, researchers in Lee’s lab engineered mice that would stop making erbB2 selectively in their heart tissue. This was necessary because earlier work had shown that “knockout” mice lacking erbB2 altogether would not come to term due to myriad developmental defects.
“In order to look at fully developed animals, which would most closely resemble patients, we set up the erbB2 gene so that it would be shut off after birth, and only in the heart,” said Steve Crone, a graduate student in Lee’s lab and co-lead author of the study.
Hearts from the mice, examined at one to six months of age, displayed clear signs of cardiomyopathy similar to those observed in Herceptin-related cardiac dysfunction.
“The enlarged heart and impaired contraction of these erbB2 mutant mice point to an unsuspected cardioprotective role for the secreted protein, neuregulin, that stimulates this receptor, ” said co-author Ken Chien, director of the Institute of Molecular Medicine at the University of California, San Diego (UCSD) and Salk adjunct professor.
“This mouse model will help us identify new mechanisms to protect patients from Herceptin cardiomyopathy, and thereby allow more aggressive and early use of Herceptin for a broad range of human cancers.”
Other physiological measurements also indicated compromised cardiac function in the mice. Cardiomyocytes – the muscle cells responsible for pumping blood through the heart – were less elastic than normal, and therefore less effective at the contraction and relaxation needed to maintain heart beat.
In addition, the erbB2 mutant mice were more susceptible than their normal counterparts to stress. They were less able to recover from tightening of the aorta, the heart’s main artery, which results in high blood pressure.
Almost all women taking Herceptin also receive or have received other anti-cancer drugs, particularly anthracyclines. Because concurrent Herceptin/anthracycline treatment increases cardiac dysfunction in patients, Lee and his colleagues examined the effects of anthracyclines on the erbB2 mutant mice.
They found that cardiomyocytes from the mice were much more sensitive to adriamycin, a commonly used anthracycline, at drug levels resembling those in patients undergoing treatment.
“Therefore, it appears that the loss of erbB2 function caused by Herceptin makes cardiac muscle more susceptible to anthracycline toxicity,” said Lee.
“These results suggest it may be appropriate to examine alternative chemotherapeutic agents in combination with Herceptin, in order to avoid the increased risk of heart disease associated with combined Herceptin/anthracycline therapy.”
Although it appears that Herceptin-related cardiomyopathy is directly related to the drug’s anti-cancer mechanism, it should be possible to design strategies to counteract the dangerous side effect.
“If we could develop agents that can stimulate the heart, particularly cardiomyocyte contractility, then those might allow you to use Herceptin aggressively while protecting the heart,” said Lee.
Efforts in Lee’s and Chien’s laboratories are focusing on this approach.
Preventing the adverse side effects of Herceptin in the heart would allow more widespread use of Herceptin for treating other forms of cancer that frequently have an abundance of erbB2, such as prostate, lung and ovarian cancers.
Co-lead author You-Yang Zhao is a postdoctoral fellow in Chien’s lab at UCSD. Additional authors include Yusu Gu, Susumu Minamisawa, Yang Liu, Kirk Peterson, Ju Chen and John Ross at UCSD; Ronald Kahn at Harvard Medical School; and Gianluigi Condorelli at Thomas Jefferson University in Philadelphia, Pa. The study, titled “ErbB2 is Essential in the Prevention of Dilated Cardiomyopathy,” was funded by the National Institutes of Health, Genentech, Inc., and the Jean Le Ducq Foundation. Chien holds an American Heart Association endowed chair. Crane is a Markey Predoctoral Fellow and a Chapman Foundation Fellow. Lee is a Pew Scholar.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. The Institute was founded in 1960 by Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.
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