Signaling pathways associated with tumorigenesis and combined treatments that alleviate drug resistance

Signaling pathways associated with tumorigenesis and combined treatments that alleviate drug resistance. Pharmaceutical CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib directly inhibit CDK4/6 activity. Moreover, the upstream mitogenic forces, including the canonical RAS-RAF-MEK-ERK pathway, heightened activity of the HER2-PI3K-AKT-mTOR axis, increase the cyclin D1 levels, activating CDK4/6 and promoting cellular progression to the S phase. Because of this foundation, PI3K, mTOR and MEK inhibitors induce synergistic anti-proliferative and pro-apoptotic effects, which lead to more durable cell cycle arrest and a delay to the onset of resistance. The Aromatase Inhibitors (AI), which inhibit the transformation of androgen into estradiol, thereby suppress breast cancer cell growth. Selective estrogen receptor modulator (SERM) and selective estrogen receptor downregulator (SERD) can affect estrogen receptors to produce the same inhibitory effect on tumor cells. ALT can keep p27 in a non-phosphorylated state, which is a stable form, and reduce both CDK2 and CDK4 activity. BMP4 and Fangchinoline can upregulate p21. Fangchinoline not only increases the level of CKIs (p21 and p27), but also inhibits cyclin D1/D3/E and CDK2/4/6. The ALT, BMP4 and Fangchinoline are still under preclinical study. In addition, clinical studies on the combination of CDK4/6 inhibitors with anti-HER2 therapy and immunotherapy are under way.

Publication

Cyclin-Dependent Kinases 4/6 Inhibitors in Breast Cancer: Current Status, Resistance, and Combination Strategies. (2019) Ying Niu, et al. J Cancer. 2019;10(22):5504-5517. Figure: F2. All organisms Homo sapiens Drosophila melanogaster Danio rerio

Disease mentions