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Figure 4. Targeting CDK 4/6 in HER2+ breast cancer. CDK4 and CDK6 play critical roles in the cell cycle. HER2 signaling or ER signaling will trigger an increase in cyclin D1 levels, which will activate CDK 4/6. Activation of the CDK 4/6 complex includes cyclin E in late G1 phase. Cyclin D1 and CDK 4/6 also phosphorylate and inactivate Rb protein, which in turn enables cell cycle progression and increase in cellular proliferation. Use of CDK 4/6 inhibitors palbociclib, ribociclib, and abemaciclib attenuates HER2-mediated induction of proliferation. Use of PI3K/Akt/mTOR inhibitors synergistically reduces cell division. Combining CDK 4/6 inhibitors with ER inhibitors or AIs can further inhibit breast cancer cell growth. Images were created using Biorender.com. CDK 4/6: cyclin-dependent kinase 4/6; EGFR: epidermal growth factor receptor; ER: estrogen receptor; HER2: human epidermal growth factor receptor 2; HER3: human epidermal growth factor receptor 3; IGF-1R: insulin-like growth factor 1 receptor; mTOR: mammalian target of rapamycin; PI3K: phosphoinositide 3-kinase; Rb: retinoblastoma protein; TSC 1/2: TSC complex subunit 1/2; AIs: aromatase inhibitors; T-DM1: trastuzumab emtansine DM1.