Dataset Information

Tracking CDK1 dynamics with a novel biosensor mouse and clinical cohorts to predict CDK4/6 inhibitor sensitivity in ER+ breast cancer

ABSTRACT: High-risk estrogen receptor positive (ER+) early breast cancer (EBC) is now managed with a combination of endocrine therapies and cyclin-dependent kinase (CDK) 4/6 inhibitors, reflecting the shift towards targeted approaches for patients with aggressive ER+ disease. Among the critical markers for high-risk EBC are high tumour grade and lymph node involvement, but currently there are no standard molecular markers in clinical practice to select these patients. In the advanced setting, ER status remains the sole molecular determinant for application of CDK4/6 inhibitors and endocrine therapies. CDK1 activity lies immediately downstream of the CDK4/6 axis, but has not been investigated as a prognostic marker for ER+ breast cancer. Here, we integrate real-time imaging of a Cdk1 activity biosensor in transgenic mice alongside high-resolution analysis of clinical cohorts to establish CDK1 as a determinant of progression and therapeutic sensitivity. Using the Cdk1 activity biosensor mouse crossed with the MMTV-PyMT;MMTV-Cre model, we imaged breast lesions and visualised in real-time Cdk1 upregulation in situ during the transition to invasive ductal carcinoma (IDC). Clinically, we identified that pCDK1T161 is specifically upregulated in IDC, and that pCDK1Y15 is prognostic of poor relapse-free survival in stage 1 disease. Critically, we uncovered a dynamic mechanism of CDK4/6 inhibitor-mediated escape. We observed that while CDK4/6 inhibition initially suppresses CDK1, activity rebounds via an adaptive response within 3 days. Analysis of the NeoPalAna trial indicates that while neoadjuvant palbociclib and anastrozole induce dynamic CDK1 regulation globally, non-responders are characterized by a failure to completely suppress CDK1 levels during treatment, or engage this early adaptive response. Furthermore, we modelled CDK4/6 inhibitor resistance in vivo and in vitro, finding that CDK4/6 inhibitor-resistant cells recovered basal CDK1 expression in vitro, and endocrine and CDK4/6 inhibitor non-responsive tumours exhibited elevated Cdk1 activity in vivo. We validated this finding in a longitudinal patient cohort where CDK1 expression was significantly increased in CDK4/6 inhibitor non-responsive tumours. Our data suggest that CDK1 is a robust biomarker for poor prognosis in early disease, and a useful indicator of adaptive responses to CDK4/6 inhibition, including the emergence of resistance. This highlights the potential of CDK1 not only as a prognostic marker but also as an alternative tool to monitor the effectiveness of CDK4/6-directed therapies and identify patients at risk of treatment failure.

ORGANISM(S): Homo sapiens

PROVIDER: GSE341330 | GEO | 2026/09/23

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Estrogen receptor-positive breast cancer (ER+BC) represent about 70% of all breast cancer cases. Approximately 30-50% of ER+BCs eventually develop resistance to primary endocrine therapy and progress to metastatic disease. The addition of cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) to endocrine therapy has improved disease control in advanced and metastatic ER+BC. However, progression on CDK4/6i is common and further research is required to fully understand and overcome the mechanisms of CDK4/6i resistance in ER+BC. We performed single-cell RNA sequencing (scRNA-seq) of temporal tumor samples from the FELINE clinical trial (NCT02712723) to uncover emergent resistance phenotypes in ER+BC patients receiving a combination of ribociclib with letrozole or letrozole alone in a neoadjuvant setting. In the majority of patient tumors, resistant cancer cells activated ErbB growth factor signaling during treatment, with an upregulation in ERBB2 and ERBB4 in post-treatment cells, as well as increased activity of transcription factors downstream of ErbB signaling. This indicates that endocrine therapy plus CDK4/6i activated compensatory ErbB growth factor signaling in resistant cells, supporting an established estrogen-independent state of proliferation. To further understand this shift in cell state, we used afatinib, an ErbB family blocker, in combination with ribociclib to target this resistance mechanism. We developed multiple in vitro three-dimensional ER+BC cell culture models that are sensitive or resistant to ribociclib. Samples were collected regularly during monotherapy or combination of ribociclib and afatinib treatment and bulk RNA-sequencing measured the dynamical changes in the cell state over short and long timescales. Generalized additive models quantitatively evaluated cancer cell plasticity and synergy of combination therapy using the RNA-seq data. Our models revealed how activity of signaling pathways drive transcriptional changes in cell cycle regulators that promote or inhibit cell cycle progression. We found that ribociclib plus afatinib synergize to promote early and sustained cell cycle arrest, and later apoptosis, in both sensitive and resistant cells. Combination therapy simultaneously restored G1/S phase regulation by inhibiting the cyclin E/CDK2 complex and enforced G2/M phase control by inhibiting the cyclin B/CDK1 complex, thereby blocking entry into mitosis. This dual inhibition strategy not only controlled cancer proliferation, but also induced caspase-dependent apoptosis. Overall, our study revealed a key CDK4/6i resistance mechanism, and demonstrated that a combination of ribociclib plus afatinib overcomes intrinsic mechanisms of resistance in ER+BC.

Dataset Information

Tracking CDK1 dynamics with a novel biosensor mouse and clinical cohorts to predict CDK4/6 inhibitor sensitivity in ER+ breast cancer

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets