Zhang Yanshuang, Wu Tingyu, Li Fan, Cheng Yirui, Han Qing, Lu Xin, Lu Shun, Xia Weiliang
State Key Laboratory of Oncogenes and Related Genes, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Front Oncol. 2022 Apr 7;12:846744. doi: 10.3389/fonc.2022.846744. eCollection 2022.
Lung squamous cell carcinoma (LUSC) remains as a major cause of cancer-associated mortality with few therapeutic options. Continued research on new driver genes is particularly important. FGF19, a fibroblast growth factor, is frequently observed as amplified in human LUSC, which is also associated with multiple genomic gains and losses. However, the importance of these associated changes is largely unknown. In this study, we aimed to clarify a novel mechanism that link neighboring oncogene co-amplification in the development of LUSC. We found that FGF19 was co-amplified and co-expressed with its neighboring gene CCND1 in a subset of LUSC patients and associated with poor prognosis. Moreover, FGF19 combined with CCND1 promoted the cell cycle progression of LUSC cells. Mechanistically, FGF19 also enhanced CCND1 expression by activating FGFR4-ERK1/2 signaling and strengthening CCND1-induced phosphorylation and inactivation of retinoblastoma (RB). In a murine model of lung orthotopic cancer, knockdown of CCND1 was found to prolong survival by attenuating FGF19-induced cell proliferation. Furthermore, the combination treatment of the FGFR4 inhibitor BLU9931 and the CDK4/6 inhibitor palbociclib potentiated the growth inhibition and arrested cells in G1 phase. , co-targeting FGFR4 and CDK4/6 also showed marked inhibition of tumor growth than single agent treatment. These findings further elucidate the oncogenic role of FGF19 in LUSC and provide insights into how the co-amplification of neighboring genes synergistically function to promote cancer growth, and combined inhibition against both FGF19 and CCND1 is more effective.
肺鳞状细胞癌（LUSC）仍然是癌症相关死亡的主要原因，治疗选择有限。持续研究新的驱动基因尤为重要。成纤维细胞生长因子FGF19在人类LUSC中经常被观察到扩增，这也与多个基因组的增减有关。然而，这些相关变化的重要性在很大程度上尚不清楚。在本研究中，我们旨在阐明一种在LUSC发生发展过程中与邻近癌基因共扩增相关的新机制。我们发现，在一部分LUSC患者中，FGF19与其邻近基因CCND1共扩增且共表达，并与不良预后相关。此外，FGF19与CCND1联合促进了LUSC细胞的细胞周期进程。机制上，FGF19还通过激活FGFR4-ERK1/2信号通路并增强CCND1诱导的视网膜母细胞瘤（RB）磷酸化和失活来增强CCND1的表达。在肺原位癌小鼠模型中，发现敲低CCND1可通过减弱FGF19诱导的细胞增殖来延长生存期。此外，FGFR4抑制剂BLU9931和CDK4/6抑制剂哌柏西利的联合治疗增强了生长抑制作用并使细胞停滞在G1期。而且，与单药治疗相比，共同靶向FGFR4和CDK4/6对肿瘤生长也显示出显著的抑制作用。这些发现进一步阐明了FGF19在LUSC中的致癌作用，并深入了解了邻近基因的共扩增如何协同作用促进癌症生长，并且联合抑制FGF19和CCND1更有效。
