Individually in fibroblast growth factor signalling pathways influences survival and identifies a novel drug resistance mechanism in ovarian cancer patients


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Lynne Sawers1, Michelle Ferguson1, Emma Joseph1, Bianca Ihrig1, Aparajitha Vaidyanathan1, Simon Herrington1, Charlie Gourley2, Roland Wolf1, Gillian Smith1
1Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, UK, 2Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK

Background

Ovarian cancer, the most common gynaecological cancer, is advanced at presentation in most patients, where treatment is rarely curative. Current treatment combines cytoreductive surgery with adjuvant or neo-adjuvant chemotherapy. While platinum-based chemotherapy is initially effective in most patients, longer-term response is frequently compromised by the development of drug resistant disease. Response to first-line treatment is therefore a significant determinant of both progression-free and overall survival.

Method

To identify novel disease progression and drug resistance mechanisms, we used qRT-PCR analysis to assess inter-tumour differences in the expression of fibroblast growth factors FGF1 and FGF2 and FGF receptors FGFR1-4 in unselected fresh-frozen and FFPE human ovarian tumours of mixed histologies (n=187), and in paired drug-sensitive and drug-resistant ovarian tumour cell lines. Gene expression was correlated with tumour histology and survival in each clinical series, and with chemosensitivity, assessed by MTT cytotoxicity assays, in tumour cell lines. Novel cell lines with stable knockdown of individual FGFs and FGFRs were created using Mission shRNA gene silencing constructs in cisplatin-resistant A2780DPP cells, which were also treated with small molecule FGFR inhibitors.

Results

FGF1 and FGFR2 were more highly expressed in high-grade serous tumours – increased FGFR2 expression was restricted to the mesenchymal FGFR2c (BEK) splice variant. In contrast, FGFR3 and FGFR4 were more highly expressed in non-serous tumours. FGF1 and FGFR2c expression was significantly inversely associated with survival (p=0.006 and p=0.04, respectively). FGF1 and FGFR2 were more highly expressed in cisplatin-resistant ovarian tumour cell lines – deletion of either gene significantly increased chemosensitivity to cisplatin and carboplatin. Similar re-sensitisation to platinum drugs was seen following combination treatment with small molecule FGFR inhibitors.

Conclusion

We have shown that key components of the FGF signalling pathway influence ovarian cancer progression and patient survival. Modulation of FGF pathway gene expression re-sensitises cisplatin-resistant cell lines, thus identifying a novel candidate drug resistance mechanism.