Researchers have discovered the missing link in a pathway that
could be targeted to block the effects of Ras, a commonly mutated
gene that drives cancer development.
Dr Axel Behrens, of the Francis Crick Institute (currently based
at Lincoln's Inn Fields), explained: "Ras is one of the most
commonly mutated genes driving cancer development. However, Ras
itself is notorious for being 'undruggable', meaning it can't be
blocked by any currently available drug.
"We therefore need to understand the complex signalling network
activated by Ras in order to tackle cancers that are driven by this
gene."
One of Ras's many effects is to switch on a set of genes
involved in cell growth by activating a factor known as AP-1.
Although researchers have known that Ras activates AP-1 for over 25
years, the molecular connection between them has been a
long-standing mystery.
Five years ago the team identified some of the key players
involved, but there were gaps in the pathway - indicating that
something was still missing. Now they have found the final piece of
the puzzle - an enzyme called Trim7.
The scientists showed that Trim7 is a type of enzyme called a
ubiquitin ligase - it controls the stability of other proteins.
They were able to pinpoint exactly how Ras signalling activates
Trim7 and found that, in fact, Trim7 can be connected back via a
chain of enzymes to Ras, and connected forward to AP-1 activation -
it completes the missing link between the two.
The team used genetic techniques to increase and decrease the
amount of Trim7 in lung cancer cells. They found that increasing
the amount of Trim7 increased the growth of lung tumours with
mutated Ras. Decreasing the amount of Trim7 reduced the growth of
lung cancer cells with mutated Ras - suggesting that mutant Ras
relies on Trim7 to maximise its tumour-driving effects.
Dr Behrens said: "Our data suggest that reducing the amount of
Trim7 could slow the growth of lung tumours that have mutations in
the Ras gene.
"Although drugs targeting Trim7 are not available, it is
possible that targeting the enzymes close to it in the chain will
also be able to interfere with this pathway and slow tumour growth.
It is also likely that Trim7 is involved in other types of cancer
with a mutated Ras gene.
"If in the future we find a drug that interferes with the Trim7
pathway, we might be able to block some of the effects of mutant
Ras in several different tumour types."
The paper, The E3 ubiquitin ligase Trim7 mediates c-Jun/AP-1 activation by Ras
signalling, is published in Nature
Communications.