ABSTRACT
Aberrant activation of the FGF19-FGFR4 signaling pathway plays an essential role in the tumorigenesis of hepatocellular carcinoma (HCC). As such, FGFR4 inhibition has emerged as a novel therapeutic option for the treatment of HCC and has shown preliminary efficacy in recent clinical trials for patients exhibiting aberrant FGF19 expression. Resistance to kinase inhibitors is common in oncology, presenting a major challenge in the clinical treatment process. Hence, we investigated the potential mechanisms mediating and causing resistance to FGFR4 inhibition in HCC. Upon the successful establishment of a battery of cellular models developing resistance to FGFR4 inhibitors, we have identified the activation of EGFR, MAPK, and AKT signaling as the primary mechanisms mediating the acquired resistance. Combination of inhibitors against EGFR or its downstream components restored sensitivity to FGFR4 inhibitors. In parental HCC cell lines, EGF treatment also resulted in resistance to FGFR4 inhibitors. This resistance was effectively reverted by inhibitors of the EGFR signaling pathway, suggesting that EGFR activation is a potential cause of intrinsic resistance. We further confirmed the above findings in vivo in mouse xenograft tumor models. Genomic analysis of patient samples from The Cancer Genome Atlas confirmed that a segment of patients with HCC harboring FGF19 overexpression indeed exhibited increased activation of EGFR signaling. These findings conclusively indicate that both induced and innate activation of EGFR could mediate resistance to FGFR4 inhibition, suggesting that dual blockade of EGFR and FGFR4 may be a promising future therapeutic strategy for the treatment of FGF19-FGFR4 altered HCC.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Animals , Mice , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Fibroblast Growth Factors/genetics , Signal Transduction , ErbB Receptors/metabolism , Cell Line, Tumor , Receptor, Fibroblast Growth Factor, Type 4/geneticsABSTRACT
INTRODUCTION: Spontaneous cerebrospinal fluid leakage is usually caused by developmental abnormalities and is rare, accounting for approximately 5% of the cases of cerebrospinal fluid (CSF) leakage. To the best of our knowledge, clival dysplasia-caused CSF rhinorrhea has never been reported in the neurosurgical field. CONCLUSION: Spontaneous cerebrospinal fluid rhinorrhea is often treated by surgery, and a transsphenoidal approach repair is the main surgical method used, offering the advantages of less trauma, fewer complications, rapid postoperative recovery, and low recurrence rate.
