The RAF-MEK-ERK pathway is often mutated in
a number of cancers, causing signals for cell proliferation and survival to be
relentlessly activated. Various inhibitors of certain components in this
pathway have been developed, but with little efficiency. It is believed that the
micro-environment of a tumour can confer a level of resistance to some cancer
therapies through the secretion of HGF, a growth factor produced by stromal
cells.
Each new
development of a treatment against cancer is met with difficulties. This study
by Straussman et al focuses on the
RAF-MEK-ERK pathway. This is a pathway through which extracellular signals are
transduced into intracellular signals, through interaction with extracellular
receptors. These signals cause the expression of transcription factors which
regulate the synthesis of genes required for cell survival and proliferation,
key genes when considering the formation of a cancer.
Previous
research has targeted the RAS protein, a component of the RAF-MEK-ERK pathway,
with unsuccessful results. This has led to research directed at the kinases
downstream from RAS. It is one of these downstream kinases investigated by
Straussman et al, in the form of RAF
and its potential inhibitors.
RAF
inhibitors (RAFis) work by interfering with the RAF protein in the RAF-MEK-ERK
pathway, preventing this pathway from transducing the signals for increased
proliferation. It has previously been seen that
inhibiting the mutated RAF reduces cancerous growth. However, these types of
responses are almost always followed by a re-emergence of that tumour, brought
on through the formation of resistance. Here it is suggested that the tumour
microenvironment may be conferring that resistance through the secretion of
soluble factors.
Whilst the
role of the microenvironment in growth and metastasis is well documented, only
recent research has suggested its function in drug resistance. In
order to test the microenvironments role in tumour drug resistance, Straussman et al began by developing a co-culture
system. In this co-culture system, GFP–labelled tumour cells were cultured
alongside stromal cells to assess modulation of drug sensitivity. This was
quantified by measuring how levels of GFP changed over a set period of time.
This test resulted in the observation that, when this co-culture system was
exposed to RAFis, those RAFis were frequently rendered ineffective when
cultured alongside stromal cells.
Strausman et al then
investigated the effect of one RAFi in particular (PLX4720). To do this they
tested the ability of stromal cell lines to provide 7 mutant BRAF (V600E) melanoma
cell lines with resistance to the anticancer drug. This resulted in six out of
the seven developing resistance to PLX4720.
It was
therefore concluded that stromal cells can
render certain anticancer drugs ineffective.
Straussman et al confirmed
that soluble factors secreted from stromal cells were responsible for the
formation of resistant tumour cells. This conformation was important, as it
allowed Straussman et al to identify
the exact resistance causing factor. To do this they conducted an
antibody-array based analysis of a large number of secreted factors. This
allowed them to compare the conditioned medium obtained from the previous 6
stromal cell lines that developed resistance to PLX4720, with stromal cell
lines that had not exhibited any sign of rescue activity.
From this,
HGF, a growth factor that plays a role in activating the receptor tyrosine
kinase MET, was identified as the source of rescue. HGF is capable of
restarting this pathway through activating MEK, bypassing the RAF component of
this pathway. Straussman et al then confirmed the presence of HGF
in a number of patients being treated with a RAFi, as well as confirming the
phosphorylation, and therefore activation of MET (See Figure).
In these
studies it is also predicted that the presence of stromal HGF in patients is a
form of innate resistance, with patients capable of producing HGF showing a
much poorer response to treatment than those unable to produce it.
However,
further evidence was required to fully confirm that the presence of HGF was the
cause of resistance. To collect this evidence, Strausmann et al tested whether recombinant HGF was capable of inducing
resistance upon tumour cells, whilst simultaneously testing whether
HGF-neutralising antibodies blocked resistance to PLX4720. This confirmed that
HGF was indeed capable of producing the resistant phenotype.
Could these results have a clinical
impact on the treatment of cancer?
These
results are important clinically in defining why certain cancer treatments
aren’t always effective, as well as identifying where research should be taken to
combat this resistance. This paper can be compared to those investigating
sorafenib, a molecular inhibitor of a number of protein kinases which has been
approved in the treatment of kidney and liver cancer.
Future
developments in this field should focus on whether the formation of resistance
can be blocked through inhibition of HGF, as well as identifying a time scale
on how long stromal cells take to confer resistance to this treatment. If this
time scale can be determined, a treatment could be developed which involves
combining therapies at specific times to amplify their effectiveness. It may
also be important to investigate further whether other RAFis are deemed
ineffective by HGF, which could make generating second generation inhibitors
important. However, it may be more prudent to investigate whether
the activation of MEK, ERK or MET can be inhibited. This would have the same
effect, but because inhibition would be taking place further along the pathway,
there is less likelihood that resistance will form.
As mentioned
by the authors, further research should also take place into investigating
whether this type of resistance has a role against other anti-cancer drugs, as
this may give us crucial information in combating against them.
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