Researchers used CRISPR genome editing to identify two genes, NADK and KHK, which markedly reduced the growth of human colorectal cancer cells with KRAS mutations when inactivated in a mouse model. The team also found new 'tumour suppressor' genes – those involved in keeping cancers at bay.
'One of the most surprising findings from our study is how performing this type of genetic screen directly in a mammalian microenvironment revealed not only new synthetic lethal interactions, but also new tumour suppressor genes that are dependent on KRAS mutations,' said Dr Edwin Yau of the University of California San Diego (UCSD), and first author of the study.
Cancers caused by KRAS mutations include lung, pancreatic and colorectal cancer - often the most lethal and difficult to treat.
While previous research has focused on directly targeting mutant KRAS proteins to treat cancer, with limited success, researchers at the UCSD's School of Medicine decided to search for other genes which kill KRAS-mutated cancer cells when inhibited.
The team used genome editing to systematically inactivate every gene in the genomes of two human colorectal cancer cell lines with and without the KRAS mutation.
They then investigated whether inactivating these genes affected the ability of the cancer cells to grow in mice.
Inhibiting NADK and KHK, which code for metabolic enzymes, reduced the growth of KRAS-mutant colorectal cancer cells in mice by about 50 percent. There was no effect on cells with normal KRAS.
Crucially, the team saw these results only when the cancer cells were grown in mice rather than in vitro. The mammalian system provides 'a more realistic microenvironment where the tumour has to survive' explained Dr Tariq Rana, who led the study.
The researchers also found other genes that, when inactivated, had the opposite effect of NADK and KHK. These tumour suppressor genes increased the growth of KRAS-mutant tumours, but not of normal KRAS tumours.
The team now want to carry out further research to better understand how KRAS-mutant cancers develop.
The study was published in Cancer Research.
The latest developments in genome editing will be discussed at the session 'What Next for Genome Editing? Politics and the Public', at the Progress Educational Trust's upcoming public conference 'Crossing Frontiers: Moving the Boundaries of Human Reproduction'.
The conference is taking place in London on Friday 8 December 2017. Full details - including sessions, speakers and how to book your place - can be found here.