{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE265nnn/GSE265952/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE265952"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"The clinical efficacy of CDK2 inhibition in CDK4/6 inhibitor-resistant HR-positive breast cancer is dependent on p53 but independent of RB","description":"Patients with hormone receptor-positive metastatic breast cancer (HR+MBC) eventually progress on CDK4/6 inhibition therapy, underscoring an unmet need for novel targeted therapies. The emergence of selective CDK2 inhibitors presents a promising advancement, positioning these agents for early clinical evaluation. Here, we analyzed tumor and liquid biopsies from patients treated with PF-07104091, the most clinically advanced CDK2 inhibitor. CDK2 inhibition monotherapy proved effective in CDK4/6 inhibitor-resistant HR+MBC patients lacking TP53 mutations. Studies in patient-derived cell lines confirmed that CDK2 inhibition efficacy is p53-dependent but unexpectedly revealed its independence from RB. Notably, we observed increased sensitivity to CDK2 inhibition in models resistant to CDK4/6 inhibitors. Unlike CDK4/6 inhibitors, CDK2 inhibition does not activate RB but rather targets DNA replication, accumulating cells in G2/M. Our findings unravel a novel mechanism of cell cycle arrest mediated through CDK2 and advocate the clinical development of CDK2 inhibitors to address resistance to CDK4/6 therapies in HR+MBC.","dates":{"publication":"2026/05/14"},"accession":"GSE265952","cross_references":{"GSM":["GSM8232525","GSM8232526","GSM8232523","GSM8232524","GSM8232521","GSM8232522","GSM8232520","GSM8232527"],"GPL":["24676"],"GSE":["265952"],"taxon":["Homo sapiens"]}}