Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Clinical Trial Center, Translational Research and Phase I Unit, ASST Spedali Civili Di Brescia, Brescia, Italy.
J Exp Clin Cancer Res. 2024 Nov 1;43(1):294. doi: 10.1186/s13046-024-03217-2.
Among blood cancers, multiple myeloma (MM) represents the second most common neoplasm and is characterized by the accumulation and proliferation of monoclonal plasma cells within the bone marrow. Despite the last few decades being characterized by the development of different therapeutic strategies against MM, at present such disease is still considered incurable. Although MM is highly heterogeneous in terms of genetic and molecular subtypes, about 67% of MM cases are associated with abnormal activity of the transcription factor c-Myc, which has so far revealed a protein extremely difficult to target. We have recently demonstrated that activation of fibroblast growth factor (FGF) signaling protects MM cells from oxidative stress-induced apoptosis by stabilizing the oncoprotein c-Myc. Accordingly, secretion of FGF ligands and autocrine activation of FGF receptors (FGFR) is observed in MM cells and FGFR3 genomic alterations represent some 15-20% MM cases and are associated with poor outcome. Thus, FGF/FGFR blockade may represent a promising strategy to indirectly target c-Myc in MM. On this basis, the present review aims at providing an overview of recently explored connections between the FGF/FGFR system and c-Myc oncoprotein, sustaining the therapeutic potential of targeting the FGF/FGFR/c-Myc axis in MM by using inhibitors targeting FGF ligands or FGF receptors. Importantly, the provided findings may represent the rationale for using FDA approved FGFR TK inhibitors (i.e. Pemigatinib, Futibatinib, Erdafitinib) for the treatment of MM patients presenting with an aberrant activation of this axis.
在血液癌症中，多发性骨髓瘤（MM）是第二常见的肿瘤，其特征是骨髓中单克隆浆细胞的积累和增殖。尽管过去几十年的特点是针对 MM 开发了不同的治疗策略，但目前这种疾病仍然被认为是无法治愈的。尽管 MM 在遗传和分子亚型方面具有高度异质性，但约 67%的 MM 病例与转录因子 c-Myc 的异常活性有关，迄今为止，这种蛋白极难成为靶点。我们最近证明，成纤维细胞生长因子（FGF）信号的激活通过稳定癌蛋白 c-Myc 来保护 MM 细胞免受氧化应激诱导的细胞凋亡。因此，在 MM 细胞中观察到 FGF 配体的分泌和 FGF 受体（FGFR）的自分泌激活，并且 FGFR3 基因组改变约占 15-20%的 MM 病例，并与不良预后相关。因此，FGF/FGFR 阻断可能代表一种有前途的策略，可以间接靶向 MM 中的 c-Myc。在此基础上，本综述旨在概述最近探索的 FGF/FGFR 系统与 c-Myc 癌蛋白之间的联系，通过使用针对 FGF 配体或 FGF 受体的抑制剂来靶向 FGF/FGFR/c-Myc 轴，为 MM 治疗提供治疗潜力。重要的是，提供的研究结果可能为使用 FDA 批准的 FGFR TK 抑制剂（即 Pemigatinib、Futibatinib、Erdafitinib）治疗存在该轴异常激活的 MM 患者提供依据。
