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Background: Clinically, the addition of CDK4/6 inhibitors (e.g. palbociclib) to endocrine therapy (ET) significantly delays progression of advanced hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer patients. However, most patients develop resistance and progress following long-term treatment. Thus, an ongoing clinical challenge has been the identification of biomarkers that predict response to CDK4/6 inhibitors. There is also an unmet need to identify actionable targets for patients who have progressed. Currently, there are no clinically useful biomarkers to predict response and/or resistance to anti-CDK4/6 therapy. Hence, the goal of our study was to identify the therapeutic vulnerabilities of CDK4/6 inhibitor resistant patient derived xenograft (PDX) models and identify key markers that longitudinally correlate with development of resistance and inform new treatment directions. Methods: We obtained 4 different PDX models, two from patients who progressed after 2-4 months on treatment with palbociclib plus ET (i.e. intrinsic resistance) and the other two who developed resistance over time (i.e. acquired resistance) with disease progression between 12-18 months while on palbociclib plus ET. To elucidate mechanisms of resistance, we performed genome-wide expression analysis via RNA-sequencing. Results: The molecular assessment of the PDX models revealed different transcriptomic signatures for intrinsic resistance compared to acquired resistance. We identified 3,386 upregulated and 2,829 downregulated significant differentially expressed genes (DEGs) in the acquired compared to intrinsic resistant PDX models. Further, gene set enrichment analysis (GSEA) revealed enrichment of distinct driver pathways in the acquired-compared to the intrinsic resistant models. Conclusions: Collectively, these results have identified potential unique targets for intrinsic and acquired resistance to guide treatment strategies. Thus, our ongoing studies are geared towards identifying and targeting distinct therapeutic vulnerabilities of intrinsic and acquired resistance to palbociclib. Citation Format: Nicole M. Kettner, Juliana Navarro-Yepes, Tuyen N. Bui, Xiayu Rao, Jing Wang, Funda Meric-Bernstam, Kelly K. Hunt, Debu Tripathy, Khandan Keyomarsi. Identifying therapeutic vulnerabilities in HR-positive, HER2-negative advanced breast cancer patient-derived xenograft models refractory to CDK4/6 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3107. |
