New Gene-Editing Strategy to Eliminate Aggressive Cancer Cells

The initiation and severity of cancer are associated with the atypical behavior of specific genes, referred to as oncogenes. The most recognized of these changes is mutation; however, it is not the sole alteration.

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Occasionally, within a single cell, an exceedingly high quantity of oncogene copies can emerge, ranging from tens to even hundreds. This amplification of oncogenes is observed in a considerable percentage of solid tumors and can enhance the aggressiveness of the tumor while hindering the body's immune system from recognizing it, thereby aiding in the emergence of treatment resistance.

A research project at the Spanish National Cancer Research Centre (CNIO) uses oncogene amplification as a weakness to combat the tumor.

The study, published in Molecular Cancer, provides proof-of-concept in animal models for eliminating tumor cells harboring amplified oncogenes via gene editing. The surplus copies of the oncogene transform into a tumor’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.

Sandra Rodríguez-Perales, Study Lead, Molecular Cytogenetics and Cancer Genome Editing Unit, Spanish National Cancer Research Centre (CNIO)

The gene-editing mechanism impacts healthy cells as well; however, due to the absence of the amplified gene, these cells are capable of repairing the induced cuts.

“This addresses one of the major bottlenecks in gene editing therapies: achieving selective cutting, so that it targets tumor cells [in this case, those with amplified oncogenes] without harming healthy cells,” stated the authors.

The novel strategy has undergone testing in cellular and animal models of neuroblastoma, small cell lung cancer, and colon cancer. These experiments demonstrated a decrease in tumor growth, an enhancement in animal survival, and alterations that may suggest an immune response capable of combating tumors.

Teaching the Immune System

Cell death may occur due to significant damage to the DNA. The hypothesis suggests that this form of cell death could signal to immune cells and enhance the activation of a response aimed at combating tumors. In their experiments, they have already observed preliminary reactions to this activation, prompting them to explore this avenue of research more deeply in their future endeavors.

“Gene editing of amplification in tumors may be a basis for developing precision gene therapies for resistant cancers,” said the authors.

They have also initiated investigations into the integration of this approach with current therapies, consistently utilizing animal models. By combining gene editing with a standard chemotherapeutic agent for neuroblastoma, they found that the number of cells undergoing apoptosis exceeded the sum of the effects of the two treatments.

“The study demonstrates a CRISPR-based novel strategy that turns oncogene amplification into a vulnerability, triggering the death only of the tumor cells, which could open up a pathway towards precision therapies for hard-to-treat tumors,” states Alejandro Nieto and Marta Martínez-Lage, the first authors of the study.