‘Drugging the undruggable’ – another step towards blocking Ras

As you may have seen in the news this week, US researchers have taken a major step towards targeting an elusive cancer molecule that has thwarted scientists for nearly 30 years.

That molecule is called Ras, a small but powerful player in cancer development and one that has been notoriously difficult to block with drugs.

Of all the molecular changes found in cancer, those that affect Ras are the most common. And these changes, known as mutations, are particularly common in lung and bowel cancer, while nearly all pancreatic cancers have hyperactive Ras.

We’ve discussed the stumbling blocks for shutting down Ras before, but this new research has made several interesting steps forward in how specific a future drug could be.

This announcement has intrigued researchers, but as always there is plenty more work to be done.

We caught up with a couple of our experts who work on Ras to get their thoughts on this promising new research.

On your marks, get set

Ras sits on the inside of a cell’s membrane primed and ready for action, like a relay sprinter waiting to receive the baton.

In the cell, the ‘baton’ is an external signal and when Ras receives that signal it triggers a relay of events resulting in genes being switched on and a change in how the cell behaves.

Normally this process is tightly controlled, with the start and end of these ‘cellular relay-races’ under strict supervision.

In cancer, mutations in Ras mean that it ‘false-starts’ and passes on signals without receiving the baton.

This happens a lot in a number of different cancers and that’s why researchers have been trying to block it for nearly 30 years.

Professor Julian Downward, one of our experts in Ras ‘relay-races’, emphasised that “finding ways to block Ras has been a major challenge.”

Ras gets switched on by a molecule called GTP, which it holds on to really tightly.

“Trying to dislodge GTP and switch off Ras has been difficult. The interaction between Ras and GTP is really strong and attempts to compete with it using drugs have been unsuccessful.”

Further attempts to block how Ras gets anchored at the cell membrane have also suffered setbacks, Professor Downward pointed out. “These inhibitors were not selective for cancer-linked changes to Ras so also blocked normal Ras,” he said.

“They affected other molecules that attach to the membrane as well. This meant that treating patients with these types of drugs would be really toxic as several normal processes in the cell would also be stopped.”

So how does this latest research differ?

A “conceptual breakthrough”

The new study adds to work we’ve covered previously that used a system called ‘fragment-based drug screening’.

Dr Martin Drysdale, one of our researchers using this approach, said: “They’ve demonstrated how the fragment-based approach can be used in clever ways to address problems we couldn’t get round before.”

Professor Downward sees this as a “conceptual breakthrough” for targeting both Ras and other ‘undruggable’ cancer molecules in the future.

The researchers seem to have hit a ‘sweet-spot’ in a number of important areas.

Setting sights on the target

Firstly, it appears that the molecules the researchers have identified only stick to a mutant form of Ras and not the normal form present in all our cells.

Professor Downward pointed out: “This is really important as it could make these molecules very selective, and has the potential to improve how patients could react to a drug.”

An important issue when trying to reduce the side effects associated with anti-cancer drugs.

Dr Drysdale said that it’s important they now focus on making sure this selectivity is as good as it can be.

“The neat thing about this new approach is they took advantage of the unique chemistry of this particular mutant form of Ras,” he said.

Hard to shake off

They used these chemical clues to produce compounds that permanently stick to Ras.

Dr Drysdale found this particularly interesting as it forms part of a renaissance for drugs that permanently stick to their target. These types of drugs have previously been thought of as bad, he said.

If a really sticky drug isn’t selective for a cancer-causing molecule they could permanently stick to the normal form too, which could make them toxic to non-cancerous cells.

“The added potential for selectively blocking a cancer-linked molecule shows that compounds that permanently stick could be beneficial,” Dr Drysdale said.

It suggests they could be a powerful blocker, which as Professor Downward points out, opens up opportunities for making any drugs that may emerge from this work particularly potent.

Ending the race

Previous attempts to make compounds that stick to Ras have faltered as they only blocked how Ras received the relay baton.

The problem with mutant Ras is it doesn’t pay much attention to whether or not it receives the correct signal.

This makes Ras ‘deaf’ to signals from the teammates above it, so blocking those signals would have very little impact on the cancer-causing properties of mutant Ras.

Critically, the new study looks to address this by also blocking how Ras passes on the baton to the rest of the team.

An important step, as the molecules Ras links up with send signals off in lots of directions, multiplying the ways in which Ras can contribute to cancer.

Blocking how well Ras sticks to some of these ‘molecular multipliers’ is an attractive way to stop it working in cancer.

Something that Professor Downward’s lab has recently been exploring.

Next in line in the Ras-race is another cancer-causing molecule called Raf.

These new compounds block how Ras and Raf interact with each other, which Professor Downward sees as an important step forward.

The future

As with any ‘first look’ at a new set of promising compounds, there is a long way to go before these become drugs that could treat patients.

This study marks a significant step forward in the 30 year challenge to make Ras ‘druggable’.

And it just goes to show the resilience of scientists working around the world to beat cancer.

Nick

Lung cancer cell image courtesy of the London Research Institute EM unit.

Ras structure image from Wikimedia Commons.

Reference

• Ostrem J.M, et al. (2013). K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions, Nature, DOI: 10.1038/nature12796