Combining tamoxifen with the protein-tyrosine kinase inhibitor dasatinib reversed the chemoresistance caused by cancer-associated fibroblasts in tissue surrounding a breast tumor, according to a report in Cell Cycle (2011;10:2521-2528).
Although approximately 70% of women diagnosed with breast cancer have estrogen receptor positive (ER[+]) disease that would be expected to respond to tamoxifen, an anti-estrogen therapy, up to one-third of those tumors have little to no response to the drug or eventually develop resistance to it. Previous animal studies have confirmed that combining anti-estrogen agents with tyrosine kinase inhibitors can prevent drug resistance, but the new research is the first to suggest that the target of the inhibitors is the fibroblasts.
Cancer cells induce aerobic glycolysis by secreting hydrogen peroxide in adjacent fibroblasts by means of oxidative stress. These cancer-associated fibroblasts then provide nutrients to tumor cells. In the current project, investigators learned that this interaction is also the basis of tamoxifen resistance, and that the combination of tamoxifen and dasatinib—a drug administered to leukemia patients who no longer benefit from any other medications—had an antioxidant effect on the fibroblasts. The combination resulted in nearly 80% cell death, which was two to three times greater than that generated by tamoxifen alone.
“The fibroblasts are what make ER(+) cancer cells resistant to the tamoxifen, but the tamoxifen plus dasatinib maintained both fibroblasts and cancer cells in a ‘glycolytic state,’ with minimal oxidative stress and more cell death, most likely because of an absence of metabolic coupling,” explained study coauthor Michael P. Lisanti, MD, PhD, in a separate statement. “The supply between the two was cut.”
Lisanti, who is professor and chair of stem cell biology and regenerative medicine at Jefferson Medical College of Thomas Jefferson University in Philadelphia, Pennsylvania; a member of the Kimmel Cancer Center at Jefferson; and a member of the editorial board of Cell Cycle, added that the findings suggest resistance to chemotherapeutic agents is a metabolic and stromal phenomenon.
In the study, the cancer cells responded to tamoxifen until they were cultured with human fibroblasts; the drug then had no effect. Dasatinib had no effect on the cancer cells or fibroblasts. “The drugs have no effect when they are used alone,” affirmed Lisanti. “It’s in unison when they effectively kill the cancer cells in the presence of fibroblasts.”