Friday, 26 April 2013

Is the inhibition of deregulated FGFRs the next step in treating cancer?


Cancer is a phenomenon that is likely to affect all of us at some point in our lives. In fact, due to the innate inefficiencies in maintaining our genetic code, if someone were to live long enough, it is inevitable that that individual would develop cancer.  It is therefore of crucial importance that new effective treatments against cancer are developed. A recent paper by Chell et al investigates the possible therapy of inhibiting unregulated fibroblast growth factors, a promising development in cancer treatment. 

Fibroblast growth factors (FGFs) function by signalling through tyrosine kinases known as Fibroblast growth factor receptors (FGFRs). FGFRs play an essential role in an organism maintaining its normal cellular behaviour in processes including cell proliferation, cell migration and cell differentiation by producing signals for growth.
In some circumstances FGFRs can become deregulated. Deregulated FGFRs are found in a large number of different types of cancers including breast and gastric cancer. By inappropriately activating FGFRs and the downstream signalling pathways, cell proliferation, survival and invasion are dramatically increased.

Because of this there has recently been a heightened interest in targeting unregulated FGFR signalling in the treatment of cancer by developing FGFR-selective tyrosine kinase inhibitors (TKIs). TKIs are drugs that inhibit the enzymes responsible for initiating the signal transduction cascades that are produced by FGFRs. 

This paper investigates the use of two specific FGFR TKIs (FGFRis). The first being AZD4547, and the second being the molecularly related AZ8010. In this instance these two compounds were compared to an FGFRi that had already been clinically established, PD173074. 

The tumour cells that were very sensitive to the action of FGFRi were found to be addicted to their deregulated FGFR signalling. This makes these tumour cells dependent on that particular pathway for cell proliferation and means that once the pathway that the tumour is addicted to is blocked, it is a struggle for a new alternative pathway to be established. Because of this they become particularly sensitive to FGFRi treatment, making it an appealing therapy in certain susceptible cancers.

If the story were to end here then the treatment of cancer wouldn’t be such a relentless challenge for researchers. However, there has also been evidence which suggests that with this type of treatment there would be a level of acquired resistance brought on by a mutation, making this therapy ineffective.  

To continue their research Chell et al attempted to model this mutation to further understand how resistance is formed. To do this they utilised the fact that the ATP binding pocket in FGFR1, 2 and 3 are highly conserved and used PD17304 in complex with FGFR1 to model the mutation that was causing them such trouble. 

The mutation responsible for resistance was at FGFRV555M in the ATP-binding site. This point mutation caused valine to be replaced by methionine. This model suggests that the bulkier side chain of Met was restricting access of FGFRis to a cavity adjacent to the adenine ring-binding protein.





In addition to this it was also noted that the equivalent residue of FGFR.Val 561 makes Van der Waals contact with the PD173074. However this isn’t true with the bigger side chain of Met561, a factor in why PD173074 can no longer bind.

This study has given a number of new insights into potential future therapies.
We can see that when FGFRs become deregulated they can act as oncogenic drivers in cancer. More importantly is the fact that some cancers can become addicted to the deregulated FGFRs that promote their high proliferation. This is important in the treatment of cancer as if there is a way of blocking this pathway of proliferation, then no new pathways of proliferation will be sought out by the tumourous cells due to this addiction.
In this particular paper resistance to FGFRis are caused by a gatekeeper mutation called FGFRV555M. However this isn’t the case in every example of FGFRi resistance, with numerous different mechanisms allowing for resistance to be acquired.

Different FGFRs have been the target of many cancer therapies in the past, and the fact that more inhibitors are becoming available is beneficial, making it even more important that the method of resistance and preventative therapies for that resistance is further investigated. When considering future studies in this field there are a number of things that need to be considered. One of these include attempting to put a timescale on when a gatekeeper mutation is likely to develop in an individual, as well as whether there is a route of therapy where this mutation will not affect the treatment.
However, at this time it may be more important to investigate a second generation of inhibitors. These will become important for when resistance to the first generation forms, making them ineffective. This has already occurred in the case of other FGFR inhibitors that have been developed in the past.

Whilst this could seem like a complicated topic, it is one that must be fully understood to contribute to the advancing field of cancer biology. The inhibition of unregulated FGFRs, whilst not being effective independently could become crucial in the chemical cocktail involved in chemotherapy, which whilst inefficient, is still a lifesaving therapy. 

How do you think this research could be taken further? Could FGFRis be become part of a new treatment used until ineffective until another drug can take its place? Comment below or email newsinscience@gmail.com with your thoughts and opinions. 

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