CDK4/6 inhibitor palbociclib enhances the effect of pyrotinib in HER2-positive breast cancer.

Human epidermal growth factor receptor 2 (HER2) is amplified in about 20% breast cancers. Treat of HER2 positive breast cancers has been greatly promoted in last few years, but the accompany HER2 blockade has hindered the therapeutic effect. Pyrotinib is a pan-HER kinase inhibitor that suppresses signaling through the RAS/RAF/MEK/MAPK and PI3K/AKT pathways. Palbociclib is a CDK4/6 inhibitor that inhibits cell cycle progression and cancer cell proliferation in ER+ breast cancers. We hypothesized that the combination of pan-HER kinase inhibitors and CDK4/6 inhibitors would show synergistic antitumor activity in vivo in vitro. Our data show that a combination of palbociclib and pyrotinib was highly synergistic in inhibiting cancer proliferation and colony formation. The combined treatment also induced significant decreases in pAKT and pHER3 activation, induced G0-G1 cell cycle arrest, and increased rates of apoptosis. In the xenograft model, the combination treatment demonstrated greater antitumor activity than either agent alone, with no apparent increase in toxicity. Our results offer a preclinical rationale clinical investigation of the effectiveness of a combination treatment of palbociclib with pyrotinib for breast cancer treatment.