Cell network maps cancer pathways

A complex intracellular network mapped by an international team of researchers could open the door to discovering new targeted treatments for colorectal cancer.

Flinders University Professor David Lynn, an EMBL Australia Group Leader at SAHMRI, jointly led the study with Professor Walter Kolch at University College Dublin in Ireland with researchers from an international collaboration including researchers in Australia, the UK, Europe and Canada.

“Like flight maps or social networks, these cellular networks involve a complex series of interactions generating an enormous number of potential pathways,” Professor Lynn says.

The team focused on interactions between proteins along what’s called the EGFR network. They performed more than 1100 analyses, mapping more than 6000 protein interactions.

“The EGFR network is the key cellular pathway that controls how cancer cells survive and grow in colorectal cancer,” Professor Lynn says.

“Our team was particularly interested in how this network is rewired within particularly nasty colorectal cancer cells that contain a mutated protein called KRAS.”

Professor Lynn and colleagues discovered the web of interactions is substantially altered within those cells.

“You can think of it like the effect of closing a major airport would have on international flight networks – flights would have to be diverted via different routes,” he says.

“Colorectal cancer patients are often treated with drugs that block this pathway but unfortunately up to 40 per cent of patients develop a mutation in the KRAS protein. The mutation causes this network to remain ‘on’ the whole time, making their cancer resistant to this drug treatment.”

While the altered pathways explain drug resistance, researchers hope they also reveal new vulnerabilities.

“We desperately need new therapeutic options to treat KRAS mutant colorectal cancer,” Professor Lynn says.

“The most significant changes we saw involved proteins that were predictive of colorectal cancer patient survival. This suggests that these proteins are really important in colorectal cancer and further research is now need to understand whether drugs to target these changes can be developed,” Professor Lynn says.

Colorectal cancers can be found in the bowel, colon or rectum. Bowel cancer is the most prevalent of these and is the second most common form of cancer for Australian men and women.

The paper, ‘Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D‘ (2020) has been published in Nature Communications DOI: 10.1038/s41467-019-14224-9

Next month, Flinders University will co-host and present at the 4th Meeting of the Federation of NeuroGastroenterology and Motility in Adelaide from 24 to 28 March 2020. Leading gut researchers from around the world will attend the week-long conference which will also delve into the latest research and development in the field.

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