Abstract 1422: Fibroblast growth factor receptor-1 is a novel therapeutic target in mantle cell Lymphoma

Abstract

Abstract Cell cycle dysregulation and significant enrichment of E2F1 target genes are hallmarks of MCL, and the inability to directly target E2F1-dependent processes is a clinical hindrance. Despite several treatment options, mantle cell lymphoma is associated with poor clinical outcomes and the development of resistance. We identified Fibroblast Growth Factor Receptor-1 is upregulated in relapsed mantle cell lymphoma patients and high FGFR-1 expression in MCL correlates with poor overall and progression-free survival. Genetic ablation of FGFR1 in MCL cells induced cell cycle arrest, and cell death in-vitro, inhibited tumor progression, and improved overall survival in-vivo. Functionally, FGFR1 loss upregulates the expression of the cell-cycle dependent Kinase inhibitor 1C (CDKN1C) through epigenetic repression via EZH2. CDKN1C binds to E2F1 and regulates the transactivation of its target genes, including CDK1. CDK1 further stabilizes MYC and positively regulates the expression of EZH2, activating the feed-forward loop to promote cell survival. Conversely, losing FGFR1 disrupts this feed-forward loop in malignant cells. This is the first report establishing FGFR1 as a novel therapeutic target and providing a rationale to target FGFR1 to treat Mantle cell lymphoma and disrupt the feed-forward loops contributing to the survival of malignant cells. Citation Format: Anuvrat Sircar, Satishkumar Singh, Ken H. Young, Narendranath Epperla, Lalit Sehgal. Fibroblast growth factor receptor-1 is a novel therapeutic target in mantle cell Lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1422.