A novel small molecule RK-019 inhibits FGFR2-amplification gastric cancer cell proliferation and induces apoptosis in vitro and in vivo

Abstract

Gastric cancer (GC) is one of the most malignant cancers and is estimated to be fifth in incidence ratio and the third leading cause of cancer death worldwide. Despite advances in GC treatment, poor prognosis and low survival rate necessitate the development of novel treatment options. Fibroblast growth factor receptors (FGFRs) have been suggested to be potential targets for GC treatment. In this study, we report a novel selective FGFR inhibitor, RK-019, with a pyrido [1, 2-a] pyrimidinone skeleton. In vitro, RK-019 showed excellent FGFR1-4 inhibitory activities and strong anti-proliferative effects against FGFR2-amplification (FGFR2-amp) GC cells, including SNU-16 and KATO III cells. Treatment with RK-019 suppressed phosphorylation of FGFR and its downstream pathway proteins, such as FRS2, PLCγ, AKT, and Erk, resulting in cell cycle arrest and induction of apoptosis. Furthermore, daily oral administration of RK-019 could attenuate tumor xenograft growth with no adverse effects. Here, we reported a novel specific FGFR inhibitor, RK-019, with potent anti-FGFR2-amp GC activity both in vitro and in vivo.

Unveiling the role of GAS41 in cancer progression

“…Late-stage diagnosis and high mortality rates highlight the urgent need for novel therapeutic targets in GC. Claudin-18.2 [ 94 ], inhibitors of the fibroblast growth factor receptor 2 (FGF2) pathway [ 95 ], and combinations of anti-angiogenesis with immune checkpoint blockade are three recognized therapeutic targets for GC [ 96 ]. It has been established that GAS41 is highly expressed in GC tissues and cell lines, and its increased expression has been linked to enhanced cell proliferation and attenuated apoptosis through activation of the Wnt/β-catenin signaling pathway [ 43 , 70 ].…”