Triple targeting of breast tumors driven by hormonal receptors and HER2.

Breast cancers that express hormonal receptors (HR) and human epidermal growth factor receptor 2 (HER2) display resistance to targeted therapy. Tumor-promotional signaling from the HER2 and estrogen receptor (ER) pathways converge at the cyclin D1 and cyclin-dependent kinases (CDKs) 4 and 6 complex, which drives cell cycle progression and development of therapeutic resistance. Therefore, we hypothesized that co-targeting of ER, HER2, and CDK4/6 may result in improved tumoricidal activity and suppress drug resistant subclones that arise on therapy. We tested the activity of the triple targeted combination therapy with tucatinib (HER2 small molecule inhibitor), palbociclib (CKD4/6 inhibitor), and fulvestrant (selective ER degrader) in HR+/HER2+ human breast tumor cell lines and xenograft models. Additionally, we evaluated whether triple targeted combination prevents growth of tucatinib or palbociclib resistant subclones in vitro and in vivo. Triple targeted combination significantly reduced HR+/HER2+ tumor cell viability, clonogenic survival, and in vivo growth. Moreover, survival of HR+/HER2+ cells that were resistant to the third drug in the regimen was reduced by the other two drugs in combination. We propose that a targeted triple combination approach will be clinically effective in the treatment of otherwise drug resistant tumors, inducing robust responses in patients.