Exploring the role of senescence induced by CDK4/6 inhibitors in resistance to breast cancer treatment.
David Tena Chaves
Centro de Investigación del Cáncer (CSIC-USAL), Salamanca
Selective cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in conjunction with endocrine therapy represent the primary adjuvant treatment approach for patients suffering with advanced or
metastatic ER-positive/HER2-negative breast cancer. Nevertheless, after a number of years of treatment, all patients inevitably develop resistance. A variety of genomic changes have been
delineated, with notable alterations in genes that govern the cell cycle or the loss of tumor suppressors. This study introduces a potential novel mechanism of resistance to CDK4/6i: senescence or enduring cell cycle arrest. CDK4/6i prompts senescence in surviving cells post-treatment. Although previously deemed irreversible, there exists scientific evidence suggesting that senescence can revert once the drug is discontinued. Furthermore, senescent cells secrete an array of factors that can facilitate tumor progression. This study seeks to assess the role of CDK4/6i-induced senescence in treatment resistance in breast cancer. To accomplish this, we will establish various CDK4/6i-resistant cell lines and scrutinize senescence and the potential for reversal of the process. Additionally, we will explore distinctions between cellular subpopulations at different stages of treatment through single-cell RNA-seq analysis. In parallel, we will investigate the impact of the secretome from senescent cells on tumor proliferation and survival, both in tumor cells and the stromal environment. The overarching objective is to identify molecules or factors originating from senescent cells implicated in treatment resistance, with the ultimate goal of uncovering therapeutic targets to aid breast cancer patients with a worse outcome to CDK4/6 inhibitor treatment.