Breast cancer tumours may take numerous paths to resist the targeted drug Herceptin, but a combination therapy could restore a tumour`s vulnerability to treatment, according to a new study.
Scientists at the University of Texas MD Anderson Cancer Center found that adding the drug saracatinib to Herceptin treatment shrinks previously resistant tumours by cutting off at least five different molecular pathways, each of which can resist.
"Scientists have identified so many ways by which a tumour resists Herceptin that it raises an important issue for treatment," said senior author Dihua Yu.
"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," she added.
Working in cell lines, mouse models of breast cancer and checking their work in human tumour 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 tumours that have a high amount of the HER2 protein.
Only about 26 per cent of women with HER2-positive breast cancer respond to Herceptin as single therapy, while 40 to 60 per cent women respond to the drug when combined with other chemotherapy.
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 favourable side effects profile.
In 2004, Yu`s lab discovered that loss of the tumour-suppressing gene known as PTEN led to Herceptin-resistant tumours.
Combining Herceptin and saracatinib to treat resistant tumours in mice reduced tumour volume by 90 per cent in 25 days.
While Herceptin alone kept tumour volume about the same during the same period, control and saracatinib alone permitted growth of more than 200 per cent.
The difference was more striking in tumours deficient in SRC`s enemy, the PTEN tumour-suppressor.
The combination reduced tumour volume by more than 90 per cent while the two drugs alone allowed growth of between 200 and 400 per cent.
The study appears in Nature Medicine.