CDK4/6: New insights into old targets

The role of CDK4/6 in promoting cell cycle progression is well known.

The role of CDK4/6 in regulating the cell cycle

The best-described function of CDK4/6 is by binding to cyclin D (cyclin D), phosphorylating retinoblastoma proteins, including RB1 and the RB-like proteins RBL1 and RBL2, ultimately activating the E2F transcriptional program and facilitating cell entry S phase of the cycle

▲ The mechanism by which CDK4/6 regulates cell cycle progression (Image source: Reference [1])

Three of the inhibitors developed based on inhibition of CDK/6 activity have been approved by the US FDA for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer, including Pfizer's palbociclib, Novartis' ribociclib and Eli Lilly's abemaciclib

The role of CDK4/6 beyond the regulation of the cell cycle

More recent studies are only beginning to reveal a role for CDK4/6 beyond regulating the cell cycle

Regulate tumor cell metabolism

Treatment of pancreatic cancer cells with CDK4/6 inhibitors results in metabolic reprogramming of tumor cells, resulting in increased mitochondrial and lysosome numbers in cells, activation of mTOR signaling and increased rate of oxidative phosphorylation

Inhibition of CDK4/6 activity may lead to an increase in the number of lysosomes in tumor cells, which is responsible for resistance to some CDK4/6 inhibitors, an effect that may reduce the clinical benefit of the inhibitors

Cyclin D3 and CDK6 promote the production of the antioxidants NADPH and GSH, which help neutralize reactive oxygen species (ROS)

Another link of CDK4/6 to metabolism and cancer is the observation of increased levels of cyclin D1 expression in obese or diabetic mice

▲The role of CDK4/6 in tumor metabolism and regulation of anti-tumor immune responses (Image source: Reference [1])

CDK4/6 inhibitors and antitumor immune responses

CDK4/6 inhibitors can modulate antitumor immune responses through direct effects on tumor cells and effects on the tumor immune environment

Inhibition of CDK4/6 activity can also have effects on the immune system by impeding the proliferation of CD4-positive FOXP3-positive regulatory T cells (Treg)

Inhibition of CDK4/6 activity can also activate effector T cells by inhibiting the NFAT-mediated signaling pathway, which can also promote the infiltration of effector T cells into tumors and cause tumor cells to upregulate PD-L1 protein expression

In triple-negative breast cancer models, CDK4/6 inhibitors combined with PI3K inhibitors can upregulate immune-related signaling pathways in tumor cells, including proteins related to antigen presentation, thereby improving tumor immunogenicity

Taken together, these studies show that CDK4/6 inhibitors may turn "cold" tumors into "hot" tumors

▲ Some clinical trials examining the combination of CDK4/6 inhibitors and immune checkpoint inhibitors, HR: hormone receptors (including estrogen and progesterone receptors); ER: estrogen receptors (Data source: Reference [1] ], by WuXi AppTec Content Team)

Looking to the future

The review pointed out that although CDK4/6 was discovered 30 years ago, attention has only begun to be paid to its role in other aspects of anti-tumor immunity

In addition, although CDK4/6 inhibitors are initially effective, patients will eventually develop resistance to them, and how to overcome the resistance is also an important research direction

The authors say that in the next few years, we will undoubtedly witness the development and testing of new CDK4/6 inhibitors

References:

[1] Fassl et al.
, (2022).
CDK4 and CDK6 kinases: From basic science to cancer therapy.
Science, https://doi.
org/10.
1126/science.
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