Researchers from the University of Colorado Denver Young Women Breast Cancer Translational Program in Aurora identified a potential triplet combination for the treatment of hormone receptor-positive (HR+) human epidermal growth factor receptor 2-positive (HER2+) breast cancer: HER2-targeted small molecule inhibitor tucatinib, CDK4/6 inhibitor palbociclib, and selective estrogen receptor blocker fulvestrant. They presented the findings at the San Antonio Breast Cancer Symposium on December 7, 2018.
The researchers cultured HR+/HER2+ human breast tumor cell lines BT474, MDA-MB-361, and UACC-812 in standard conditions. They generated subclones of tucatinib- and palbociclib-resistant BT474 and MDA-MB-361 by culturing cells in increasing concentrations of the inhibitors over six months. Using CellTiter-Glo®, the researchers performed cell survival assays after 72 hours of treatment with just the vehicle; tucatinib, palbociclib, and fulvestrant as single agents; and dual and triple combinations.
Dual combination of tucatinib plus fulvestrant and tucatinib plus palbociclib were synergistic in all three HR+/HER2+ cell lines. The addition of fulvestrant further improved tumor cell death in all three breast tumor cell lines. The combination of tucatinib and palbociclib resulted in greater suppression of phospho-AKT and total and phospho-CDK2 compared to either agent alone. Use of tucatinib or palbociclib alone significantly increased cyclin E expression at 48 and 72 hours after treatment; however, the result was not observed after dual treatment with tucatinib plus palbociclib.
Cross-treatment of cells resistant to palbociclib plus tucatinib suppressed cell growth and decreased the expression of phospho-ERK1/2, phospho-AKT, phospho-CDK2, and cyclin E.
The triplet treatment “demonstrated significant synergy, potentially acting through suppression of phospho-AKT and cyclin E pathways, therefore suggesting a promising novel approach to treatment of HR+/HER2+ breast cancer,” the researchers concluded. They continue to test the triplet regimen in an ongoing phase IB/II clinical trial.