4.7 Article

CDK4/6 inhibitors induce breast cancer senescence with enhanced anti-tumor immunogenic properties compared with DNA-damaging agents

Journal

MOLECULAR ONCOLOGY
Volume -, Issue -, Pages -

Publisher

WILEY
DOI: 10.1002/1878-0261.13541

Keywords

CDK4/6 inhibitors; DNA-damaging agents; SASP; therapy-induced senescence; tumor microenvironment

Categories

Ask authors/readers for more resources

This study compared the senescence induced by cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with that induced by conventional DNA-damaging agents. The results showed that both types of agents caused a similar degree of senescence, but DNA-damaging agents increased the expression of senescence-associated secretory phenotype (SASP) and ligands related to pro-tumor immunity and angiogenesis. CDK4/6i-induced senescent cells maintained the expression of anti-tumor immunomodulatory proteins at a similar or higher intensity compared to cells treated with DNA-damaging agents, despite the absence of nuclear factor-kappa-B (NF-kappa B) and p53 activation.
Since therapy-induced senescence (TIS) can either support or inhibit cancer progression, identifying which types of chemotherapeutic agents can produce the strongest anti-tumor TIS is an important issue. Here, cyclin-dependent kinase4/6 inhibitors (CDK4/6i)-induced senescence was compared to the TIS induced by conventional DNA-damaging agents. Despite both types of agents eliciting a similar degree of senescence, we observed increased expression of the senescence-associated secretory phenotype (SASP) and ligands related to pro-tumor immunity (IL6, CXCL8, TGF beta, CD274, and CEACAM1) and angiogenesis (VEGFA) mainly in TIS induced by DNA-damaging agents rather than by CDK4/6i. Additionally, although all agents increased the expression of anti-tumor immunomodulatory proteins related to antigen presentation (MHC-I, B2M) and T cell chemokines (CXCL9, 10, 11), CDK4/6i-induced senescent cells still maintained this expression at a similar or even higher intensity than cells treated with DNA-damaging agents, despite the absence of nuclear factor-kappa-B (NF-kappa B) and p53 activation. These data suggest that in contrast with DNA-damaging agents, which augment the pro-tumorigenic microenvironment via pro-inflammatory SASP, CDK4/6i can generate TIS only with antitumor immunomodulatory proteins.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available