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LncRNA EILA promotes CDK4/6 inhibitor resistance in breast cancer by stabilizing cyclin E1 protein.

ABSTRACT: CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy are now standard first-line therapy for advanced HR⁺/HER2^- breast cancer, but developing resistance is just a matter of time in these patients. Here, we report that a cyclin E1-interacting lncRNA (EILA) is up-regulated in CDK4/6i-resistant breast cancer cells and contributes to CDK4/6i resistance by stabilizing cyclin E1 protein. EILA overexpression correlates with accelerated cell cycle progression and poor prognosis in breast cancer. Silencing EILA reduces cyclin E1 protein and restores CDK4/6i sensitivity both in vitro and in vivo. Mechanistically, hairpin A of EILA binds to the carboxyl terminus of cyclin E1 protein and hinders its binding to FBXW7, thereby blocking its ubiquitination and degradation. EILA is transcriptionally regulated by CTCF/CDK8/TFII-I complexes and can be inhibited by CDK8 inhibitors. This study unveils the role of EILA in regulating cyclin E1 stability and CDK4/6i resistance, which may serve as a biomarker to predict therapy response and a potential therapeutic target to overcome resistance.

SUBMITTER: Cai Z

PROVIDER: S-EPMC10558131 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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LncRNA EILA promotes CDK4/6 inhibitor resistance in breast cancer by stabilizing cyclin E1 protein.

Cai Zijie Z Shi Qianfeng Q Li Yudong Y Jin Liang L Li Shunying S Wong Lok Lam LL Wang Jingru J Jiang Xiaoting X Zhu Mengdi M Lin Jinna J Wang Qi Q Yang Wang W Liu Yujie Y Zhang Jun J Gong Chang C Yao Herui H Yao Yandan Y Liu Qiang Q

Science advances 20231006 40

CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy are now standard first-line therapy for advanced HR<sup>+</sup>/HER2<sup>-</sup> breast cancer, but developing resistance is just a matter of time in these patients. Here, we report that a cyclin E1-interacting lncRNA (EILA) is up-regulated in CDK4/6i-resistant breast cancer cells and contributes to CDK4/6i resistance by stabilizing cyclin E1 protein. EILA overexpression correlates with accelerated cell cycle progression and poor prognosis in br ...[more]

PMID: 37801505

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Project description:Breast cancer (BC) is the most common cause of cancer-related death in women worldwide. Therapies targeting molecular pathways altered in BC had significantly enhanced treatment options for BC over the last decades, which ultimately improved the lives of millions of women worldwide. Among various molecular pathways accruing substantial interest for the development of targeted therapies are cyclin-dependent kinases (CDKs)-in particular, the two closely related members CDK4 and CDK6. CDK4/6 inhibitors indirectly trigger the dephosphorylation of retinoblastoma tumor suppressor protein by blocking CDK4/6, thereby blocking the cell cycle transition from the G1 to S phase. Although the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib gained FDA approval for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative BC as they significantly improved progression-free survival (PFS) in randomized clinical trials, regrettably, some patients showed resistance to these therapies. Though multiple molecular pathways could be mechanistically responsible for CDK4/6 inhibitor therapy resistance, one of the most predominant ones seems to be the fibroblast growth factor receptor (FGFR) pathway. FGFRs are involved in many aspects of cancer formation, such as cell proliferation, differentiation, and growth. Importantly, FGFRs are frequently mutated in BC, and their overexpression and/or hyperactivation correlates with CDK4/6 inhibitor resistance and shortened PFS in BC. Intriguingly, the inhibition of aberrant FGFR activity is capable of reversing the resistance to CDK4/6 inhibitors. This review summarizes the molecular background of FGFR signaling and discusses the role of aberrant FGFR signaling during cancer development in general and during the development of CDK4/6 inhibitor resistance in BC in particular, together with other possible mechanisms for resistance to CDK4/6 inhibitors. Subsequently, future directions on novel therapeutic strategies targeting FGFR signaling to overcome such resistance during BC treatment will be further debated.

Dataset Information

LncRNA EILA promotes CDK4/6 inhibitor resistance in breast cancer by stabilizing cyclin E1 protein.

Publications

LncRNA EILA promotes CDK4/6 inhibitor resistance in breast cancer by stabilizing cyclin E1 protein.

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