The onset and aggressiveness of cancer are related to the abnormal behaviour of certain genes, known as oncogenes. The best-known of these alterations is mutation, but it is not the only one. Sometimes, within a cell, a very high number of copies of the oncogene appear – tens or even hundreds. This amplification of oncogenes occurs in a significant proportion of solid tumours and may make the tumour more aggressive and prevent the body's defences from detecting it, contributing to the development of resistance to treatments.
A study led by Sandra Rodríguez-Perales, head of the Molecular Cytogenetics and Cancer Genome Editing Unit at the Spanish National Cancer Research Centre (CNIO), and by Raúl Torres, from the Innovative Therapies Unit at CIEMAT, uses the amplification of oncogenes as a vulnerability to fight the tumour.
Published in Molecular Cancer, the study offers proof of concept in animal models to destroy tumour cells containing amplified oncogenes through gene editing. Thus, the excess copies of the oncogene become a tumour's Achilles' heel.
Cutting to the root of the problem: the oncogene
"We used the CRISPR-Cas9 gene editing tool to make a cut in the amplified oncogene. Normally, when a cell detects damage in its DNA, it repairs it; but if the gene is amplified and exists in multiple copies, the cut occurs in all of them and a high level of genetic damage builds up. As it lacks the capacity to fully repair it, the cell triggers its cell death machinery," Rodríguez explains.
The gene editing mechanism also affects healthy cells, but since they do not have the amplified gene, they can repair the cuts made.
"This addresses one of the major bottlenecks in gene editing therapies: achieving selective cutting, so that it targets tumour cells [in this case, those with amplified oncogenes] without harming healthy cells," the authors state.
The new strategy has been tested in cellular and animal models of neuroblastoma, small cell lung cancer and colon cancer. These experiments saw a reduction in tumour growth, an increase in animal survival, and changes that may indicate a tumour-fighting immune response.
Teaching the immune system
Cell death would be induced by high levels of damage to the DNA. The team's hypothesis is that this type of cell death could alert the immune cells and promote the activation of a tumour-fighting response. In their experiments, they have already detected initial reactions to this activation, so they will delve further into this line of research in future work.
"Gene editing of amplification in tumours may be a basis for developing precision gene therapies for resistant cancers," the authors say.
They have also begun to explore the combination with existing therapies, always in animal models. By combining gene editing and one of the common drugs used in chemotherapy for neuroblastoma, they observed that the number of cells that died was larger than the sum of those caused by the two treatments separately. Alejandro Nieto and Marta Martínez-Lage, the first authors of the study, state that "the study demonstrates a CRISPR-based novel strategy that turns oncogene amplification into a vulnerability, triggering the death only of the tumour cells, which could open up a pathway towards precision therapies for hard-to-treat tumours."
Funding
This study has received public funding from the National Plan for Research and Innovation, the Carlos III Health Institute, and FEDER funds, as well as private funding from the Spanish Cancer Association (AECC).
About the National Cancer Research Centre (CNIO)
The National Cancer Research Centre (CNIO) is a public research centre under the Department of Science, Innovation and Universities. It is the largest cancer research centre in Spain and one of the most important in Europe. It includes around five hundred scientists, along with support staff, who are working to improve the prevention, diagnosis and treatment of cancer.
