Targeting drug resistance in breast cancer: a dual-perspective landscape analysis of PROTACs from bench to bedside.

BACKGROUND

Acquired therapy resistance, particularly endocrine resistance in estrogen receptor-positive (ER +) breast cancer, remains a major clinical challenge. Proteolysis-targeting chimeras (PROTACs) have emerged as a novel therapeutic paradigm with the potential to overcome resistance by degrading target proteins. This study provides a comprehensive landscape analysis of PROTACs in breast cancer, synthesizing research trends and clinical trial progress to map the path from discovery to application.

METHODS

We conducted a dual-perspective analysis. Bibliometric data from 350 publications (Web of Science Core Collection) were analyzed to delineate the research evolution, collaboration networks, and target focus. Concurrently, 30 clinical trials registered on ClinicalTrials.gov were systematically reviewed to evaluate the clinical translational stage, target distribution, and safety profiles of PROTACs in breast cancer.

RESULTS

Research output has grown exponentially since 2016, led by China and the United States. The estrogen receptor (ER) is the predominant target in both basic and clinical research. Clinical development is advancing rapidly, with the ER degrader ARV-471 reaching phase III trials. In patients with ER + /HER2 - advanced breast cancer and ESR1 mutations, ARV-471 demonstrated a median progression-free survival of 5.0 months, doubling that achieved with fulvestrant (2.1 months). While fatigue and nausea are common adverse events, the overall safety profile appears manageable. However, clinical exploration remains highly concentrated on ER + disease, with limited progress in other subtypes such as HER2 + and triple-negative breast cancer.

CONCLUSIONS

PROTACs, especially ER degraders, suggest a potential strategy for addressing endocrine resistance in advanced ER + breast cancer, as reflected in encouraging preliminary clinical data. This integrated analysis highlights the rapid translation of this technology while underscoring the critical need to expand target scope, address inherent resistance mechanisms, and broaden applications to other breast cancer subtypes. Our article synthesizes current knowledge and trial landscape, thereby providing a consolidated foundation to inform future research and clinical development of PROTACs in breast cancer.