New approach shines light on how genes drive cancer
Despite significant advances, our mechanistic understanding of how specific cancer-causing genes transform cells is still limited.
A collaboration led by Monash Biomedicine Discovery Institute (BDI) researcher, Professor Roger Daly, has made fresh insights into this process by applying a global perspective to the role of a particular class of signalling enzyme called protein kinases. Importantly, the approach used can also identify improved therapeutic strategies for cancer, in this case an aggressive form of breast cancer.
The study, which has spanned six years, was underpinned by a strong collaboration between Professor Daly and Associate Professor Kaylene Simpson, Head of the Victorian Centre for Functional Genomics at the Peter MacCallum Cancer Centre. The results have just been published in Nature Communications.
Professor Daly said that while the functional role and clinical relevance of a subset of protein kinases was well-established, a significant proportion of the entire complement of human protein kinases, known as the ‘kinome’, was poorly characterised. This was partly due to the tendency of researchers to follow the road well-travelled, he said.
The researchers broadened their enquiries, making their study global and unbiased.
They exploited a technique called mass spectrometry that enabled them to look at all the protein kinases expressed in a cell and determine what the effect of a particular oncogene – in this case Src – was on these. This was important because Src is implicated in several human cancers, include those of the breast, colon and lung.
The scientists identified kinases regulated by Src then launched a second phase of the project, coupling the initial kinase screens done by mass spectrometry to functional genomic screens, taking all the protein kinases affected by Src and knocking down their expression in the cancerous cells. This identified which ones were important for Src to drive the cancer.
“In doing this we were able to identify ten protein kinases critical for the ability of the oncogene to make the cell cancerous,” Professor Daly said.
The researchers looked at one of these – SGK1 – in considerable detail and showed that the regulation of SGK1 by Src was important in triple negative breast cancer, making SGK1 a therapeutic target.
“The approach integrating mass spectrometry-based proteomics with functional genomics gave us incredible insight into the mechanisms of how this particular oncogene drives cancer,” he said.
“The findings also enable you to identify new therapeutic strategies which exploit this information.
“We were able to identify SGK1 as a therapeutic target in triple negative breast cancer and also show that if you apply a combination therapy that targets both Src and SGK1 it’s actually better than targeting either protein alone.”
The approach used in the proof-of-principle study has since been applied to other oncogenes and tumour suppressors, including a study in prostate cancer.
Professor Daly is now working with Professor Christina Mitchell, an author on the paper, to apply it to certain tumour-suppressor genes she is working on in breast cancer.
First authors on this study are Xiuquan (Hugh) Ma and Luxi Zhang.
Read the full paper in Nature Communications titled Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation.
About the Monash Biomedicine Discovery Institute
Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.