Panoply™ Human FGFR4 Over-expressing Stable Cell Line

Lung adenocarcinoma accounts for approximately half of all lung cancer cases. Between 20% and 50% of these tumors carry mutations affecting the expression or activity of the epidermal growth factor receptor (EGFR), which can serve as therapeutic targets. EGFR inhibitors have shown significant efficacy in this regard and are currently used clinically. However, not all adenocarcinomas carrying EGFR mutations respond to treatment, thus necessitating the search for biomarkers to predict treatment outcomes and the development of novel therapies that enhance the sensitivity of these tumors to EGFR inhibitors. Here, researchers describe a synergistic effect between EGFR and FGFR4, leading to mutual activation and pro-cancer consequences both in vitro and in vivo. This synergistic effect is independent of EGFR-activating mutations and enhances resistance to different EGFR inhibitors. At the therapeutic level, researchers provide evidence that the combined use of EGFR and FGFR inhibitors has a synergistic effect on tumors with high FGFR4 expression and EGFR activation, both in vitro and in vivo. Consistent with these results, the study found that patients treated with EGFR inhibitors experienced earlier recurrence when tumors exhibited high FGFR4 expression.

Researchers found that, compared to control cell lines, EGFR-activated, FGFR4-overexpressing cell lines exhibited higher resistance to two different EGFR inhibitors, erlotinib and osimertinib, while showing higher sensitivity to two selective FGFR inhibitors, BGJ398 and AZD4547. However, these effects were not observed in the other three non-EGFR-activated adenocarcinoma cell lines (Figure 1A). To explore the synergistic effect of EGFR-FGFR4 in vitro from a therapeutic perspective, researchers treated EGFR-activated, FGFR4-overexpressing cells with all possible combinations of the aforementioned EGFR and FGFR inhibitors to evaluate the effect of dual inhibition of the two receptors on cell viability. The results showed that dual inhibition of EGFR-FGFR had a synergistic effect, but this was only observed in FGFR4-overexpressing cells (Figure 1B). Since the combination of erlotinib and AZD4547 was the most effective, this inhibitor combination was chosen for subsequent experiments. Next, the oncogenic signaling pathways in the H1975 and HCC827 cell lines treated with erlotinib/AZD4547 were evaluated (Figure 1C). In FGFR4-overexpressing cell lines, combination therapy was more effective at inhibiting the EGFR signaling pathway than erlotinib alone. Similar effects were observed in p42/p44. In the HCC827 cell line, dual inhibition of FGFR and EGFR further suppressed the AKT signaling pathway compared to erlotinib alone, but no such effect was observed in the H1975 cell line.

Figure 1. In vitro effects of FGFR4 overexpression on EGFR and FGFR inhibitor sensitivity. (Quintanal-Villalonga A, et al., 2019)