BACR1
An FGFR inhibitor prevents chemoresistance in vitro and in vivo: a novel therapy for small cell lung cancer
Olivier E. Pardo1, Claire Ashwin1, Gordon Stamp1, Nicholas Lemoine2, Michael J. Seckl1
1Imperial College London, London, UK, 2St Barts Hospital, London, UK
Small cell lung cancer (SCLC) represents 15-20% of lung cancer with overall survival ≤5% at 3 years due to the development of chemoresistance. We have previously shown that fibroblast growth factor-2 (FGF-2) induces proliferation and chemoresistance in SCLC cells. Consequently, we investigated whether the selective FGFR inhibitor PD0173074 could block these effects in vitro and in vivo.
Here we found that this inhibitor blocked H-510 and H-69 SCLC proliferation and clonogenic growth in a dose dependent fashion with an IC50 in the low nanomolar range. In addition, PD0173074 prevented FGF-2-induced chemoresistance. These effects correlated with the inhibition of both FGFR1 and 2 transphosphorylation and downstream MEK/Erk signalling. We then performed experiments using daily oral administration of PD0173074 for 28 days in two human SCLC models. In the H-510 xenograft, tumour growth was impaired similar to that seen with single-agent cisplatin administration, increasing median survival compared to control sham-treated animals. Crucially, the effect of cisplatin was significantly potentiated by co-administration of PD0173074. An even more dramatic effect was seen with H-69 xenografts where this agent induced complete responses lasting greater than 6 months in 50% of mice. This action correlated with reduced FGFR phosphorylation and increased apoptosis in excised tumours. Moreover, in vivo imaging with 18FLT-PET showed decreased intra-tumoral DNA synthesis in live animals treated with the compound at 7-14 days.
Our results suggest that clinical trials of FGFR inhibitors should be undertaken in patients with SCLC and that 18FLT-PET imaging could provide early in vivo evidence of response.
