Drug resistance reversed when tamoxifen is paired with antimalarial agent

The antimalarial drug hydroxychloroquine (HCQ) reverses resistance to tamoxifen in mice, reported investigators from Georgetown Lombardi Comprehensive Cancer Center.

In the June 15 issue of Clinical Cancer Research,

The investigators found that adding HCQ to tamoxifen could provide a new treatment option for some women with advanced, postmenopausal estrogen receptor-positive (ER+) breast cancer. Tamoxifen blocks estrogen from fueling the tumor; however, tumors will either not respond or will become resistant to tamoxifen over time in 50% of cases.

Previous research by the study's senior investigator, Robert Clarke, PhD, DSc, dean for research at Georgetown University Medical Center, and Katherine Cook, PhD, a postdoctoral research fellow in the tumor biology department at Georgetown Lombardi, found that tamoxifen resistance occurs because a pro-survival pathway is switched on in breast cancer cells. HCQ functions by turning off that very same molecular pathway.

HCQ was developed to treat malaria, but is also used as therapy for rheumatoid arthritis and lupus. In this study, the research team purposely set out to test HCQ in mice with either tamoxifen- or faslodex-resistant human breast cancer cells. The study is the first to test HCQ's ability to restore breast cancer cell sensitivity to tamoxifen or to fulvestrant (Faslodex), a different antiestrogen drug.

"Tamoxifen resistance when treating breast cancer is a big issue in the clinic, and we believe our findings provide a very promising fix to the problem," said Clarke, who is also co-director of the breast cancer program at Georgetown Lombardi. In addition, Clarke noted that both drugs are inexpensive, on the market, and have a well-defined safety profile.

The researchers found that the combination of tamoxifen and HCQ is more effective than Faslodex and HCQ due to activities within the tumor's microenvironment. “Faslodex and tamoxifen, while both effective as antiestrogen therapies, have different effects on the immune system thus making the combination of faslodex and HCQ less effective,” says Cook.


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