Identifying New Cancer Drug Targets
Computation Network Modelling Proves a Useful Tool for Identifying New Cancer Drug Targets
Researchers at Systems Biology Ireland (SBI) at University College Dublin have identified what they believe to be a streamlined method of tracking and predicting how mutations in KRAS genes change protein interactions in colorectal cancer cells.
In a paper titled “Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D,” SBI scientists, together with an international consortium from Australia, Europe and Canada, explain the intracellular network they have studied which will hopefully lead to new, more targeted cancer treatments. The paper was published on 24th January 2020 in the scientific journal, Nature Communications.
“We know that gene mutations cause cancer, but we don't know what these mutations are actually doing and how they change cells so that they become cancer cells,”
said Prof. Walter Kolch, Director of Systems Biology Ireland (SBI) and corresponding author on the paper.
“This study lifts the curtain on how mutations in one of the most frequently altered culprits in human cancer, the KRAS gene, change protein interaction networks in colorectal cancer cells. The results are mindboggling. A single mutation in KRAS is associated with widespread protein interaction changes which rewires about one third of all connections. The result is a very profound change in information flow through this network which reprograms gene expression turning the cell into a cancer cell. Understanding these fundamental mechanisms how mutations actually impact cellular functions is the first and prerequisite step towards developing better and more efficacious cancer drugs.”
Using quantitative mass spectrometry, the researchers analysed more than 1,000 protein complexes and mapped more than 6,000 protein interactions along the epidermal growth factor receptor (EGFR) network.
“The EGFR network is the key cellular pathway that controls how cancer cells survive and grow in colorectal cancer,”
said Prof. David Lynn, an EMBL Australia Group Leader at SAHMRI and Flinders University and corresponding author.
“Like flight maps or social networks, these cellular networks involve a complex series of interactions generating an enormous number of potential pathways,” he said.
“Interactions define the interplay of proteins within a cell and thereby how signalling networks are organized. In a comparative analysis of networks and by integrating multiple data types, we demonstrate how oncogenic mutation highjack these networks by extensive rewiring,”
said Dr. Karsten Boldt, corresponding author from the Institute for Ophthalmic Research at the Eberhard-Karls University of Tuebingen.
“I think that our unique approach can, in future, be applied to further networks and will help to understand the molecular basis of various diseases,” he said.
Other SBI authors include SBI authors include Susan Kennedy ('17), Cinzia Raso ('16), Theodosia Charitou ('17), Carlos Herrera-Montavez ('16), Aleksandar Krstic, David Gomez Matallanas, Christina Kiel, Nora Rauch, Oleksii Rukhlenko, Boris Kholodenko, Luis Iglesias-Martinez, Colm Ryan and Ruth Pilkington.
The ultimate hope of the researchers in this study is to garner a better understanding of RAS signalling and mutations, which, when paired with computational network modelling strategies in the screening process, will lead to eventual increased drug success and cancer treatment.
Kolch also revealed that Nature Communications will also be publishing a blog piece corresponding with the research article. The blog, titled "The ripple effects of a RAS mutation," was written by Walter Kolch and David Lynn and gives additional perspective on the study and its history.
“Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D” ; Nature Communications 2020 The article will be available on the journal website.
Nature Communications is an open access journal that publishes high-quality research from all areas of the natural sciences. Papers published by the journal represent important advances of significance to specialists within each field.