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

Abstract

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, TGFβ, 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-κB) 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: Dong Hyun Lee, Muhammad Imran, Jae Ho Choi, Yoo Jung Park, Young Hwa Kim, Sunwoo Min, Tae Jun Park, Yong Won Choi
• Journal: Molecular oncology (Mol Oncol) Vol. 18 Issue 1 Pg. 216-232 (Jan 2024) ISSN: 1878-0261 [Electronic] United States
• PMID: 37854019 (Publication Type: Journal Article)
• Copyright: © 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Chemical References

• NF-kappa B
• CDK4 protein, human
• Cyclin-Dependent Kinase 4

Topics

• Humans
• Female
• Breast Neoplasms (drug therapy, pathology)
• NF-kappa B (metabolism)
• Cellular Senescence (genetics)
• Tumor Microenvironment
• Cyclin-Dependent Kinase 4