Abstract 2809: Targeting the LINC00355-MENIN interaction with CDK4/6 inhibitors to reduce proliferation in late relapse breast cancer

Abstract Breast cancer is the most common cancer diagnosed among women in the United States, with approximately 310,720 new cases estimated in 2024. Late relapse refers to disease recurrence after being disease-free for at least five years following the initial curative treatment. Late relapse is particularly relevant to ER+/HER2- breast cancer as it accounts for over 50% of recurrences for patients with this subtype of breast cancer. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in combination with endocrine therapy are standard first-line therapy for metastatic relapse. While these therapies initially show promise, resistance to endocrine therapy and CDK4/6 inhibitors inevitably develops, presenting a major clinical challenge and unmet medical need for late relapse. Long non-coding RNAs (lncRNAs) are key regulators of cancer-related processes, including cell cycle progression. Our lab has identified deregulated lncRNAs in metastatic late relapse breast cancer patient tumor samples, but their role in CDK4/6 inhibitor resistance remains unclear. To investigate this, we treated the ER+ primary breast cancer cell line MCF7 (wild-type) and the long-term estrogen-deprived (LTED) cell line - mimicking late relapse with CDK4/6 inhibitors, including Abemaciclib, Palbociclib, and Ribociclib. Wild-type cells were more sensitive to these inhibitors than LTED cells. Further, the analysis identified that LINC00355, the topmost upregulated lncRNA in late relapse breast cancer binds to the MENIN protein. This was demonstrated using RNA pulldown assays and multiplexed RNA in situ hybridization in LTED cells and patient samples. The LINC00355-MENIN interaction decreases CDKN1B expression, promoting cellular proliferation. Notably, MENIN has been shown to regulate the CDK4/6 pathway and inhibit cell proliferation. To explore the therapeutic potential, we reduced LINC00355 expression using GapmeRs, locked nucleic acid-based antisense oligonucleotides (LNA ASOs), which significantly decreased cell proliferation. In contrast, treatment of LTED cells with Palbociclib or Ribociclib alone for 72 hours showed no significant changes in proliferation. However, combination treatment with LINC00355 LNA ASOs and Palbociclib or Ribociclib resulted in a notable reduction in cell proliferation. These findings highlight the critical role of lncRNA-protein interactions, such as LINC00355-MENIN, in promoting cellular proliferation and provide proof-of-concept for targeting lncRNAs that can cause resistance to CDK4/6 inhibitors for late relapse breast cancer. Citation Format: Richa Mishra, Brianna Duhart, Dhanusha Duraiyan, Prasanth Thunuguntla, Kyla Gelev, Debbie C. Crans, Cynthia X. Ma, Jessica Silva-Fisher. Targeting the LINC00355-MENIN interaction with CDK4/6 inhibitors to reduce proliferation in late relapse breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2809.