Uncontrolled cell growth is a hallmark of cancer. One of the
most important signalling pathways that regulates the growth and
survival of cancer cells is called the PI3-kinase
pathway.
Now, scientists at Cancer Research UK's London Research
Institute (LRI; now part of the Francis Crick
Institute) have identified a completely new way in which the
PI3-kinase pathway is be activated in some cancers, including many
melanomas, providing a potential new treatment
target.
Julian Downward of LRI explained: "The majority of cancers
harbour changes in the PI3-kinase pathway, and intense efforts are
underway to develop PI3-kinase inhibitors for cancer treatment.
Some of these are now in clinical trials and showing potentially
promising early results.
"There are, however, major challenges to overcome, including
serious side effects of these drugs and the development of
resistance to them. A key strategy to tackle both problems is to
find out exactly how PI3-kinases are regulated. This will allow us
to specifically target harmful parts of the pathway while sparing
others, and to understand how drug resistance
emerges."
There are four related but distinct versions (called isoforms)
of PI3-kinase, although most tissues only have two: a and b. While
both of these are important in cancer, Professor Downward's team
focused on studying the b isoform because its function and the way
it's regulated is surprisingly different from the other
isoforms.
RAS proteins are 'molecular switches' that frequently have
mutations that cause them to be overactive in cancer - causing
uncontrolled cell growth. Looking at the interaction between RAS
proteins and PI3-kinases, the scientists unexpectedly found that,
unlike the a isoform, the b isoform is not regulated by RAS
proteins. Instead, the b isoform is directly regulated by a distant
relative of RAS called RAC, which controls the ability of cells to
change shape and move.
Professor Downward explained: "These findings are important
because they show that the b isoform of PI3-kinase does not need to
be targeted in cancers carrying mutations in RAS (around 25 per
cent of all cancers).
"However, RAC proteins have also been implicated in certain
cancers, especially melanoma, where they might be important in
promoting the spread of the cancer to other sites in a patient's
body."
He concluded: "This direct link between RAC and PI3-kinase
suggests that specifically blocking the b isoform of PI3-kinase
might be a promising strategy in some cancers."
The paper, RAS
and RHO families of GTPases directly regulate distinct
phosphoinositide 3-kinase isoforms, is published
inCell.