‘Drugging the undruggable’ – another step towards blocking Ras

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mutant Ras

Source: Cancer Research UK Science Blog

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….READ FULL ARTICLE




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