Fibroblast Growth Factor Signalling: From Development to Cancer

Nicholas Turner; Richard Grose

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In This Article

Future Prospects

The past decade has seen a dramatic increase in our understanding of the relevance of FGFs and their receptors to cancer biology. Depending on the tumour type, aberrant FGF signalling can function in a cell-autonomous fashion, or through modulating tumour–stroma interactions, and activate different downstream pathways depending on cellular context. The emerging data on FGF signalling has sparked several pharmaceutical companies to develop drugs that target FGFRs. These are now entering the clinic, and many more are in preclinical development.

It is currently not well understood how FGFR2 signalling can be tumour promoting in some contexts, but tumour suppressive in others. Until the underlying mechanisms of the context specificty of FGF signalling are better understood, the non-selective targeting of FGFRs should be used cautiously in an adjuvant or curative setting. An assessment of the safety of long-term FGFR inhibition in preclinical models would be reassuring. The mechanisms underlying tumour suppressive effects could, however, also present an opportunity in cancer treatment. The potentiation or reinstatement of these FGF-mediated tumour suppressive signals may represent a new avenue in tumour therapy.

The presence of many different genomic aberrations, each one largely specific to the tumour type and often occurring at a low frequency, presents practical problems for clinical development. Successful strategies will depend on the selection of tumours in which FGF signalling is driving proliferation and survival, and it is likely that a set of tumour-specific companion diagnostics will be required to select patients. This becomes a more difficult problem when identifying tumours in which paracrine and autocrine signalling is driving tumour cell proliferation. Although the activation of signalling loops will be highly prevalent in some tumour types, for other types it will be a challenge to differentiate tumours in which changes in FGFR receptor expression and splicing are driving proliferation from those in which these changes occur merely as consequence of tumour progression. The identification of tumours in which FGF2 is driving angiogenesis presents a similar problem. Much translational research is required to help address these questions. It is also likely that additional tumour types that are driven by FGF signalling, with different mechanisms of FGF pathway activation, will emerge in the next few years to further strengthen the role of FGF signalling in cancer biology.

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