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    • br Acknowledgments This study was supported

    2021-10-25


    Acknowledgments This study was supported by a Conquer Cancer Foundation (American Society for Clinical Oncology) Drug Development Research Professorship Grant (AAA).
    Introduction Gastric cancer (GC) is one of difficult cancers to treat in terms of its poor prognosis and limited applicability of anti-cancer therapeutic agents. Amplification of fibroblast growth factor receptor2 (FGFR2) has been one of genomic aberrations to be targeted, for its role as a driver of tumorigenesis and its relatively frequent incidence in GC (Cancer Genome Atlas Research, 2014; Hierro et al., 2017; Touat et al., 2015). FGFR is a receptor tyrosine kinase (RTK) family comprising four members, FGFR1, FGFR2, FGFR3, and FGFR4 (Eswarakumar et al., 2005). FGFR signaling is initiated by interaction with 23 different FGF ligands, and it is involved in many cellular processes, including proliferation, differentiation, migration, angiogenesis, and embryonic development (Eswarakumar et al., 2005; Klint and Claesson-Welsh, 1999; Touat et al., 2015). Several in vitro and in vivo studies have shown a critical role of amplified FGFR2 in the carcinogenesis of GC. A previous study reported that suppression of FGFR2 kinase activity by a specific small-molecule inhibitor resulted in growth inhibition and induction of apoptosis in a series of FGFR2-amplified GC cell lines (Kunii et al., 2008). Suppression of tumor growth by oral administration of a TKI to GC mouse xenograft models overexpressing FGFR2 supported the role of FGFR2 signaling in tumorigenesis (Takeda et al., 2007). In addition, tumor growth of xenografts of SNU-16 GC Licofelone mg harboring FGFR2 amplification was inhibited by intraperitoneal injection of a monoclonal antibody against FGFR2 (Zhao et al., 2010). Analyses of clinical data again suggested the potential of FGFR2 as a therapeutic target in treatment of GC by showing poor prognosis in patients with the genomic aberrance of FGFR2 (Betts et al., 2014; Su et al., 2014). Given the considerable devotion of deregulated FGF/FGFR signaling to the oncogenesis of GC, many anticancer agents targeting the signaling pathway have been developed. AZD4547, one of selective FGFR inhibitors that inhibits tyrosine kinase activity of FGFR 1–3, has demonstrated efficacy in tumor control of FGFR-deregulated in vivo models and cell lines (Gavine et al., 2012; Xie et al., 2013). Although the potential antitumor activity of AZD4547 has been supported by pre-clinical data and has culminated into clinical trials, development of resistance to small-molecule inhibitors by cancers remains an issue (Hierro et al., 2017; Van Cutsem et al., 2017). Several previous studies have tried to clarify the mechanisms of resistance against FGFR inhibitors in FGFR-dependent cell lines. Development of mutations in the FGFR2 kinase domain resistant to FGFR inhibitors is one of suggested resistance mechanisms. A previous study reported that 14 mutations resistant to dovitinib were identified in FGFR2-overexpressing BaF3 cells after culture with the pan-FGFR inhibitor (Byron et al., 2013). Chell et al. identified a heterozygous mutation, V555M, at the gatekeeper residue of FGFR3, cross-resistant to AZD4547 in KMS-11 myeloma cells (Chell et al., 2013). In addition to acquiring somatic mutations, activation of alternative RTKs and subsequent intracellular signal transduction leading to resistance to FGFR inhibitors is another often reported theory. in vitro studies of FGFR2-amplified GC cells showed that cells with multiple activated RTKs were hyposensitive to AZD4547 (Chang et al., 2015). A high-throughput platform assay for secreted proteins also demonstrated bypass signaling pathways turned on by ligand-mediated activation of alternative RTKs (Harbinski et al., 2012). The Eph receptor, a RTK family comprising 16 receptors, is known to play a crucial role in embryonic development by directing cell migration and positioning, axon guidance, and tissue morphogenesis (Park and Lee, 2015). Although the role of Eph receptor-ephrin signaling in oncogenesis is still controversial, several studies report aberrant expression of Eph receptor in various cancers and implicate its involvement in cancer progression (Ji et al., 2011; Miyazaki et al., 2013; Zelinski et al., 2001). A previous study reported overexpression of EphB3 in non-small cell lung cancer (NSCLC) and its contribution to cell growth and migration using the EphB3 overexpressing in vivo model, indicating the involvement of EphB3 signaling in promoting epithelial to mesenchymal transition (EMT) (Ji et al., 2011). EMT is a biological process by which epithelial cells with polarity gain the phenotype of mesenchymal cells through multiple biochemical transformations, rendering those cells to obtain the capacity of migration and invasiveness (Kalluri and Weinberg, 2009). EMT has been shown to play a function in development of resistance to various TKI in cancer cells (Rho et al., 2009; Yauch et al., 2005). In fact, a previous in vitro study reported EMT-mediated resistance in AZD4547-treated FGFR2-amplified GC cells, although definitive alternative signaling pathways that induced EMT were not elucidated (Grygielewicz et al., 2016).