Abstract
Abstract Introduction: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, including palbociclib, ribociclib, and abemaciclib, have revolutionized the treatment of estrogen receptor-positive (ER+) breast cancer. However, the development of resistance to these inhibitors poses a formidable challenge in the clinical management of ER+ breast cancer. This study aims to explore the common resistance mechanisms in three CDK4/6 inhibitor-resistant models induced by chronic exposure to these agents. Methods: We developed models of resistance to palbociclib, ribociclib, and abemaciclib by repeatedly exposing murine xenografts to these CDK4/6 inhibitors. Resistance was confirmed through cell viability assays and in vivo tumorigenesis studies. The tumors were sequenced using NGS analyses, and genes of interest were validated through Western blotting and qPCR. Results: In all resistant models, we identified a common resistant mechanism via NGS analyses, which was characterized by the overexpression of the FAT1, CCNE1, and AR genes. The upregulation of these genes at mRNA and protein levels was confirmed by qPCR analyses and western blotting, respectively. Our data indicate that upregulation of FAT1, CCNE1, and AR genes may play a critical role in mediating resistance to CDK4/6 inhibitors, namely palbociclib, ribociclib, and abemaciclib. Conclusion: Our investigation uncovered a shared mechanism, characterized by the overexpression of FAT1, CCNE1, and AR genes, that underlay CDK4/6 inhibitors-induced drug resistance in ER+ breast cancer. These findings shed light on the shared pathways that drive CDK4/6 inhibitor resistance and provide insights into potential therapeutic targets for overcoming this resistance in breast cancer patients. Understanding these mechanisms is crucial for the development of more effective treatment strategies for CDK4/6 inhibitor-resistant cancers. Citation Format: Bin Li, Gaoxiang Liu, Ting Ni, Wenting Shi, Qingyang Gu. Unveiling mechanisms of CDK4/6 inhibitor resistance in ER+ breast cancer models with acquired resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5871.
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