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RAS proteins – common, cancer-causing, and can’t be drugged?

08
May
2015

Could indirect lines of attack be the key to hitting one of cancer’s most elusive targets?

Posted on 08 May, 2015 by Andy Roast

Drugs that target specific cancer proteins offer the hope of more effective treatments with fewer side-effects than conventional chemotherapy. But some proteins are harder to target than others – and some of them are common cancer proteins implicated in many different types of the disease.

One cancer in five contains faults in genes coding for a group of molecules known as ‘RAS proteins’. These are important components of cellular signalling and have a role in controlling the growth and copying of cells. The genes coding for these proteins were the first cancer-causing genes – oncogenes – to be discovered. In the 1980s, Professors Chris Marshall and Alan Hall from The Institute of Cancer Research in London discovered one of these genes – NRAS – along with the mechanism by which it and other RAS-family oncogenes make cells cancerous.

But despite their prevalence in human cancers, and the length of time with which researchers have had to study them, there are still no drugs that specifically target RAS proteins directly.

Many researchers are now looking for clever, indirect ways to target cancers caused by these mutations. In a recent review paper, Professor Julian Downward, who is Associate Research Director of the Francis Crick Institute and also works at the ICR, offered an overview of the ways in which these proteins may be targeted.

Combining different drugs to target numerous protein products of RAS is one of the methods discussed. However, combining therapies often leads to increased toxicity and Professor Downward points out that there is only one example of a combination of drugs shown to be effective against a member of the RAS family (KRAS).  Instead, Professor Downward reviews progress made on synthetic lethality – targeting proteins which the cancer cell has become dependent on because of its RAS mutations.

The ICR has a strong record of exploiting synthetic lethality. Professor Alan Ashworth, who was Chief Executive of the ICR until last year, showed how cancers containing BRCA1 and BRCA2 mutations are dependent on PARP proteins, which are involved in DNA repair. This work helped in the development of the drug olaparib – a PARP inhibitor which is approved for use in treating women with ovarian cancer who carry BRCA mutations (and is showing early promise in treating men with prostate cancer).

Professor Downward discusses a number of studies that have targeted RAS through synthetic lethal approaches. The research has followed two basic ideas – researchers have either ‘switched RAS mutations on and off’ in cell lines, or they have tested a panel of drugs on a range of cells from patients containing varying degrees of mutation.

Both methods allow scientists to uncover fundamental differences between cells with a RAS mutation and those without – knowledge which could lead to more targeted treatments in the future. But these approaches do have their flaws, notably that cancer cells in patients often contain many more gene mutations than cell lines used in the lab and are therefore much more complex beasts to drug.

Professor Downward writes in the review article published in Clinical Cancer Research, “This may be a good point at which to step back and evaluate what has been achieved. Unfortunately, [synthetic lethality] has yet to provide much basis for optimism.”

So, it seems RAS remains the elusive target it always has been. However, Professor Downward is optimistic about the potential for using modern screening techniques on larger groups of cells or on more realistic cell-based models of cancer as it occurs in patients. By screening more cells, with more mutations, researchers may then finally be able to deliver drugs that are effective against this challenging group of proteins.
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