Promising new target for melanoma treatment

23 May 2013

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.

  • Researchers studying a molecular pathway that's implicated in cancer have discovered a promising new treatment target for certain types of cancer, particularly melanomas. 
  • The PI3-kinase pathway is already under investigation for cancer treatment with drugs already undergoing clinical trials. However side effects and drug resistance are a concern. The results from the current study may offer a way to target a different part of this pathway with the possibility of sidestepping these problems. 
  • Melanoma is a type of skin cancer that can develop from abnormal moles. Almost 13,000 new cases of melanoma were recorded in 2010 in the UK.