Combination overcomes breast cancer resistance to herceptin

Breast cancer tumors take numerous paths to resist the targeted drug Herceptin, but a single roadblock at a crucial crossroads may restore a tumor's vulnerability to treatment, scientists at The University of Texas MD Anderson Cancer Center report on line at Nature Medicine.

Adding the drug saracatinib to Herceptin treatment shrinks previously resistant tumors by cutting off at least five different molecular pathways, each of which can resist, said senior author Dihua Yu, M.D., Ph.D., professor in MD Anderson's Department of Molecular and Cellular Oncology.

"Scientists have identified so many ways by which a tumor resists Herceptin that it raises an important issue for treatment," Yu said. "Will we have to give patients six drugs or 10 drugs to block them all? The side effects would be awful. Two pills are better. This combination is a promising therapy for those with Herceptin-resistant breast cancer."

Working in cell lines, mouse models of breast cancer and checking their work in human tumor samples, Yu and colleagues identified SRC, a known cancer-promoting protein, as the crucial common downstream component of multiple resistance pathways.

Saracatinib is an SRC inhibitor, thwarting that protein and allowing Herceptin to work again in tumors that have a high amount of the HER2 protein.

Only about 26 percent of women with HER2-positive breast cancer respond to Herceptin as single therapy. Between 40 and 60 percent respond to the drug when combined with other chemotherapy.

Combination is ready for clinical trials

Yu said saracatinib has been tested in phase I and phase II clinical trials as a single treatment against late-stage cancers. It has a favorable side effects profile.

"It didn't work as a single agent, but very few drugs work by themselves against late stage disease," Yu said. "Our experiments confirmed its lack of efficacy as a sole treatment. But combined with Herceptin, it's beautiful."

Another SRC inhibitor, dasatinib, has been approved by the U.S. Food and Drug Administration as an anti-cancer drug, but it has harsher side effects, said Siyuan Zhang, Ph.D., a postdoctoral fellow in Yu's lab and the paper's first author.

A tumor-suppressor's job

In 2004, Yu's lab discovered that loss of the tumor-suppressing gene known as PTEN led to Herceptin-resistant tumors. PTEN is a phosphotase - a protein whose function is to strip phosphate chemical groups off of other molecules.

PTEN has two components, one to remove phosphate groups from lipids, and another to remove them from proteins. PTEN's target protein however, was unknown.

Zhang discovered that SRC is a PTEN target. With its phosphate groups, SRC is active. PTEN stifles SRC by peeling away the phosphates.

If PTEN loss leads to Herceptin resistance, and PTEN targets SRC, would that make SRC the culprit?