EGFR Inhibition Overcomes Resistance to FGFR4 Inhibition and Potentiates FGFR4 Inhibitor Therapy in Hepatocellular Carcinoma.

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.

P2Y6 contributes to ovalbumin-induced allergic asthma by enhancing mast cell function in mice.

Extracelluar nucleotides have been identified as regulatory factors in asthmatic pathogenesis by activating purinergic receptors. This research aimed to investigate the function of the purinergic receptor P2Y6 in mediating airway inflammation in allergic asthma. Wild-type (WT) and P2Y6-deficient mice were stimulated with ovalbumin (OVA) to construct asthmatic mouse models. Overexpression of P2Y6 and uridine 5'-diphosphate (UDP)-releasing were demonstrated in lung tissues in ovalbumin-induced asthmatic mice. The release of the cytokine IL-4, mast cell invasion, and the airway remodeling phenotypes were more severe following the application of UDP in asthmatic mice. However, P2Y6 deficiency reduced these asthmatic pathogeneticsymptoms markedly in a mouse model. In vitro, we found that P2Y6 in purified mast cells enhanced the functions of mast cells in the inflammatory response in the asthmatic process by triggering their capability for migration, cytokine secretion and granule release. Moreover, P2Y6 stimulated the function of mast cells through activation of the AKT signaling pathway. Our data provides evidence that P2Y6 contributes to allergic airway inflammation and remodeling by enhancing the functions of mast cells in ovalbumin-induced asthmatic mice.

Gpr97 Is Dispensable for Inflammation in OVA-Induced Asthmatic Mice.

BACKGROUND: Asthma is a complex inflammatory disorder involving the activation and invasion of various immune cells. GPR97 is highly expressed in some immunocytes, including mast cells and eosinophils, which play critical roles in asthma development. However, the role of Gpr97 in regulating airway inflammation in asthma has rarely been reported. In this study, we investigated the potential role of Gpr97 in the development of allergic asthma in mice. METHODS: Relevant airway asthmatic mouse models were constructed with both wild-type and Gpr97-/- mice sensitized to 250 µg ovalbumin (OVA). The levels of interleukin IL-4, IL-6 and IFN-γ, which are involved in OVA-induced asthma, in the bronchoalveolar lavage fluid (BALF) and the IgE level in the serum were examined by enzyme-linked immunosorbent assay (ELISA). The invasion of mast cells and eosinophils into lung tissues was assessed by immunohistochemical and eosinophil peroxidase activity assays, respectively. Goblet cell hyperplasia and mucus production were morphologically evaluated with periodic acid-Schiff (PAS) staining. RESULTS: In our study, no obvious alteration in the inflammatory response or airway remodeling was found in the Gpr97-deficient mice with OVA-induced asthma. Neither the secretion of cytokines, including IL-4, IL-6 and IFN-γ, nor inflammatory cell recruitment was altered in the Gpr97-deficient mice. Moreover, Gpr97 deficiency did not affect airway remodeling or mucus production in the asthma mouse model. CONCLUSION: Our findings imply that Gpr97 might not be required for the development of airway inflammation in OVA-induced allergic asthma in mice.