Cyclin-dependent kinase 4/6 inhibitors in breast cancer (Homo sapiens)

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Description

"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." Source: Figure F2 in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775706. Derived from https://pfocr.wikipathways.org/figures/PMC6775706__jcav10p5504g002.html.

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Bibliography

  1. Niu Y, Xu J, Sun T; ''Cyclin-Dependent Kinases 4/6 Inhibitors in Breast Cancer: Current Status, Resistance, and Combination Strategies.''; J Cancer, 2019 PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
135825view01:37, 13 November 2024EweitzAdd nodes, improve arrangement
135822view13:03, 12 November 2024EweitzAdd more nodes
135821view13:02, 12 November 2024EweitzAdd more nodes
135820view12:29, 12 November 2024EweitzImport PI3K / AKT nodes
135818view05:01, 12 November 2024EweitzImport RAS / MEK / ERK nodes
135817view01:26, 12 November 2024EweitzNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AKT1GeneProductENSG00000142208 (Ensembl)
AKT2GeneProductENSG00000105221 (Ensembl)
AKT3GeneProductENSG00000117020 (Ensembl)
CCND1GeneProductENSG00000110092 (Ensembl) "Cyclin D1" originally
CCNE1GeneProductENSG00000105173 (Ensembl)
CDK2GeneProductENSG00000123374 (Ensembl)
CDK4GeneProductENSG00000135446 (Ensembl)
CDK6GeneProductENSG00000105810 (Ensembl)
CDKN1AGeneProductENSG00000124762 (Ensembl) "p21" originally
CDKN1BGeneProductENSG00000111276 (Ensembl) "nonphorphorylated p27" originally. Also in original caption: "Fangchinoline not only increases the level of CKIs (p21 and p27)".
EGFRGeneProductENSG00000146648 (Ensembl)
ERBB2GeneProductENSG00000141736 (Ensembl)
HRASGeneProductENSG00000174775 (Ensembl)
IGF1RGeneProductENSG00000140443 (Ensembl) "IGFR" originally
KRASGeneProductENSG00000133703 (Ensembl)
MAP2K1GeneProductENSG00000107356 (Ensembl)
MAP2K2GeneProductENSG00000101418 (Ensembl)
MAP2K3GeneProductENSG00000107958 (Ensembl)
MAP2K4GeneProductENSG00000115669 (Ensembl)
MAP2K5GeneProductENSG00000138015 (Ensembl)
MAP2K6GeneProductENSG00000129652 (Ensembl)
MAP2K7GeneProductENSG00000118907 (Ensembl)
MAPK1GeneProductENSG00000100030 (Ensembl)
MAPK3GeneProductENSG00000102882 (Ensembl)
NRASGeneProductENSG00000213281 (Ensembl)
PIK3C2AGeneProductENSG00000011405 (Ensembl)
PIK3C2BGeneProductENSG00000133056 (Ensembl)
PIK3C2GGeneProductENSG00000139144 (Ensembl)
PIK3CAGeneProductENSG00000121879 (Ensembl)
PIK3CBGeneProductENSG00000051382 (Ensembl)
PIK3CDGeneProductENSG00000171608 (Ensembl)
PIK3CGGeneProductENSG00000105851 (Ensembl)
PIK3R1GeneProductENSG00000145675 (Ensembl)
PIK3R2GeneProductENSG00000105647 (Ensembl)
PIK3R3GeneProductENSG00000117461 (Ensembl)
PIK3R4GeneProductENSG00000196455 (Ensembl)
PIK3R5GeneProductENSG00000141506 (Ensembl)
PIK3R6GeneProductENSG00000276231 (Ensembl)
RAF1GeneProductENSG00000132155 (Ensembl)

Annotated Interactions

No annotated interactions

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