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Introduction: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) represent the standard of care for patients with oestrogen receptor-positive (ER+) metastatic breast cancer (MBC). However, a significant proportion of patients either present intrinsic resistance or acquired resistance over time, limiting the clinical benefit of these treatments. Understanding the molecular mechanisms driving resistance and identifying effective second-line therapies remain major clinical challenges. Objectives: The main objectives of this study are: 1) To generate and characterise patient-derived xenograft (PDX) models from tumor biopsies collected before and after treatment with CDK4/6i+ET. 2) To investigate mechanisms of intrinsic and acquired resistance to CDK4/6i+ET using genomic, transcriptomic, proteomic and epigenetic approaches. Methodology: A total of 17 PDX models were established from ER+ breast cancer patients treated with CDK4/6i+ET. These models were comprehensively characterised through targeted exome sequencing (IMPACT-MSKCC), PAM50-based transcriptomic classification, and immunohistochemistry. To evaluate drug response, PDXs were treated with CDK4/6i (Ribociclib or Abemaciclib) in combination with ET (Letrozole + ovariectomy or the oral SERD Elacestrant). Models that initially responded were further chronically exposed to treatment to induce acquired resistance, mimicking clinical progression. Results: Among the 17 PDX models, 8 showed intrinsic resistance while 9 were initially sensitive to CDK4/6i+ET. Acquired resistance was successfully generated in several initially sensitive models through continuous in vivo drug exposure. Molecular profiling identified both known and novel alterations associated with resistance, including mutations in NOTCH2, supporting its potential role as a resistance driver. These findings highlight the heterogeneity of resistance mechanisms and underscore the importance of individualised approaches. Conclusions: PDX models derived from ER+ MBC patients constitute a valuable preclinical platform to explore both intrinsic and acquired resistance to CDK4/6i+ET. These models not only recapitulate clinical phenotypes but also enable the identification of predictive biomarkers and the testing of targeted therapies. Our study provides mechanistic insights and supports the use of PDXs to develop personalised treatment strategies aimed at overcoming resistance in hormone receptor-positive metastatic breast cancer.