套细胞淋巴瘤
癌症研究
成纤维细胞生长因子受体1
生物
体内
淋巴瘤
细胞生长
医学
成纤维细胞生长因子
免疫学
内科学
受体
遗传学
生物技术
作者
Anuvrat Sircar,Satishkumar Singh,Zijun Y. Xu-Monette,Krysta M. Coyle,Laura K. Hilton,Evangelia Chavdoula,Parvathi Ranganathan,Neeraj Jain,Walter Hanel,Philip N. Tsichlis,Lapo Alinari,Blake R. Peterson,Jianguo Tao,Natarajan Muthusamy,Robert A. Baiocchi,Narendranath Epperla,Ken H. Young,Ryan D. Morin,Lalit Sehgal
出处
期刊:Leukemia
[Springer Nature]
日期:2023-08-19
卷期号:37 (10): 2094-2106
被引量:2
标识
DOI:10.1038/s41375-023-02006-8
摘要
Abstract Mantle cell lymphoma (MCL) is a lethal hematological malignancy with a median survival of 4 years. Its lethality is mainly attributed to a limited understanding of clinical tumor progression and resistance to current therapeutic regimes. Intrinsic, prolonged drug treatment and tumor-microenvironment (TME) facilitated factors impart pro-tumorigenic and drug-insensitivity properties to MCL cells. Hence, elucidating neoteric pharmacotherapeutic molecular targets involved in MCL progression utilizing a global “unified” analysis for improved disease prevention is an earnest need. Using integrated transcriptomic analyses in MCL patients, we identified a Fibroblast Growth Factor Receptor-1 (FGFR1), and analyses of MCL patient samples showed that high FGFR1 expression was associated with shorter overall survival in MCL patient cohorts. Functional studies using pharmacological intervention and loss of function identify a novel MYC-EZH2-CDKN1C axis-driven proliferation in MCL. Further, pharmacological targeting with erdafitinib, a selective small molecule targeting FGFRs, induced cell-cycle arrest and cell death in-vitro, inhibited tumor progression, and improved overall survival in-vivo. We performed extensive pre-clinical assessments in multiple in-vivo model systems to confirm the therapeutic potential of erdafitinib in MCL and demonstrated FGFR1 as a viable therapeutic target in MCL.
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