For breast cancer tumours that have developed resistance to the drug trastuzumab (Herceptin®) combining treatment with saracatinib could offer a strategy to overcome resistance conferred by multiple mechanisms, reports a US study in Nature Medicine.

Rationally designed targeted therapies are widely believed to represent the future of personalised medicine for cancer patients. Trastuzumab is a humanized antibody targeting HER2 receptors which has shown considerable clinical efficacy and extended the overall survival of certain patients with HER2 expressing tumours. The reality, however, is that only around 26 % of women with HER2-positive breast cancers respond to trastuzumab as single therapy, and that 40 to 60 % respond when used in combination with systemic chemotherapy. The reason for the small response, it is thought, is the development of multiple resistance mechanisms.

Working in cell lines, mouse models of breast cancer and checking their work in human tumour samples, Dihau Yu and colleagues from The University of Texas MD Anderson Cancer Center (Houston, USA) identified SRC, a known cancer promoting protein as the crucial common downstream component of multiple resistance pathways. Saracatinib is a known SRC inhibitor that thwarts the protein and allows trastuzumab to work again in tumours with high amounts of HER2 proteins.

In the study Yu and colleagues showed that saracatinib cuts of five different molecular pathways, each of which is known to play a role in resistance. Furthermore they showed that combining trastuzumab with saracatinib to treat resistant tumours in mice reduced tumour volumes by 90 % over 25 days.

Saracatinib has already been tested in phase I and II clinical treatments as a single treatment against late-stage cancers where it was shown to have a favourable side effects profile.

"Our studies identified SRC activation as a key convergence point of multiple trastuzumab resistance mechanisms. The combinatorial regimen of SRC inhibitor plus trastuzumab is effective in overcoming various de novo and acquired resistance mechanisms," conclude the authors, adding that their findings may directly impact the management of patients HER2 over expressing breast cancers.

Giving combinations of six or 10 drugs to block or the ways by which tumours resist trastuzumab would just not be feasible. "The side effects would be too awful. Two drugs would be far better," said Yu.

Article: S Zhang, W Huang, P Li et al. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nature Medicine. Doi:10.1038/nm.2309