The fibroblast growth factor receptor inhibitor PD173074 blocks small cell lung cancer growth in vitro and in vivo.
Lung cancer is the commonest cancer killer. Small cell lung cancer (SCLC) is initially chemosensitive, but rapidly relapses in a chemoresistant form with an overall survival of <5%. Consequently, novel therapies are urgently required and will likely arise from an improved understanding of the disease biology. Our previous work showed that fibroblast growth factor-2 induces proliferation and chemoresistance in SCLC cells. Here, we show that the selective fibroblast growth factor receptor (FGFR) inhibitor PD173074 blocks H-510 and H-69 SCLC proliferation and clonogenic growth in a dose-dependent fashion and prevents FGF-2-induced chemoresistance. These effects correlate with the inhibition of both FGFR1 and FGFR2 transphosphorylation. We then determined the efficacy of daily oral administration of PD173074 for 28 days in two human SCLC models. In the H-510 xenograft, tumor growth was impaired similar to that seen with single-agent cisplatin administration, increasing median survival compared with control sham-treated animals. Crucially, the effect of cisplatin was significantly potentiated by coadministration of PD173074. More dramatically, in H-69 xenografts, PD173074 induced complete responses lasting >6 months in 50% of mice. These effects were not a consequence of disrupted tumor vasculature but instead correlated with increased apoptosis (caspase 3 and cytokeratin 18 cleavage) in excised tumors. Moreover, in vivo imaging with 3'-deoxy-3'-[(18)F]fluorothymidine-positron emission tomography ([(18)F]FLT-PET) showed decreased intratumoral proliferation in live animals treated with the compound at 7 to 14 days. Our results suggest that clinical trials of FGFR inhibitors should be undertaken in patients with SCLC and that [(18)F]FLT-PET imaging could provide early in vivo evidence of response.
Pardo
Olivier E
OE
Lung Cancer Biology Group, Cancer Research UK Laboratories, Clinical Sciences Centre, Hammersmith Hospital Campus of Imperial College London, London, United Kingdom.
Latigo
John
J
Jeffery
Rosemary E
RE
Nye
Emma
E
Poulsom
Richard
R
Spencer-Dene
Bradley
B
Lemoine
Nick R
NR
Stamp
Gordon W
GW
Aboagye
Eric O
EO
Seckl
Michael J
MJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004357:Drug Synergism; D016222:Fibroblast Growth Factor 2 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D049268:Positron-Emission Tomography; D011743:Pyrimidines / Q000494:pharmacology*; D017468:Receptors, Fibroblast Growth Factor / Q000187:drug effects* / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C115711:PD 173074; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D002945:Cisplatin