Oncogenes & Cancer: Gene Editing Targets Amplification for New Therapies

The development and aggressiveness of cancer are linked to abnormal behavior in specific genes, known as oncogenes. While mutation is the most recognized alteration, it isn’t the only one. Sometimes, a cell contains a dramatically increased number of copies of an oncogene – dozens, even hundreds.

Unlocking a Tumor’s Weakness

This amplification of oncogenes is found in a significant proportion of solid tumors and can contribute to a tumor becoming more aggressive, harder for the body’s defenses to detect, and resistant to treatments. Now, research is exploring a novel approach: exploiting this very amplification as a vulnerability.

Did You Know? The research team utilized the CRISPR-Cas9 gene editing tool to target amplified oncogenes, aiming to trigger cell death.

A study led by Sandra Rodríguez-Perales, head of the Molecular Cytogenetics and Cancer Genome Editing Unit at the National Cancer Research centre (CNIO), and Raúl Torres, from the Innovative Therapies Unit at CIEMAT, utilizes oncogene amplification as a target to combat the tumor. Published in Molecular Cancer, the study demonstrates a proof of concept in animal models for destroying tumor cells containing amplified oncogenes. In this approach, the excess copies of the oncogene become a tumor’s “Achilles heel.”

Cutting to the Core of the Problem

“We used the CRISPR-Cas9 gene editing tool to make a cut in the amplified oncogene,” explains Rodríguez. “Normally, when a cell detects damage to 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 accumulates. Unable to repair it completely, the cell activates the cell death machinery.”

The gene editing mechanism also affects healthy cells, but these cells, lacking the amplified gene, can repair the induced cuts. “We are thus addressing one of the major bottlenecks of gene editing therapies: achieving selectivity, so that it attacks tumor cells – in this case, those with the amplified oncogene – without damaging healthy cells,” the authors state.

Promising Results in Animal Models

This new strategy has been tested in cellular and animal models of neuroblastoma, small cell lung cancer, and colorectal cancer. Experiments showed a reduction in tumor growth, increased animal survival, and changes suggesting an anti-tumor immune response.

Expert Insight: This research represents a significant step toward precision oncology, potentially allowing therapies to target a specific vulnerability present in cancer cells while sparing healthy tissue. The selective targeting achieved through exploiting oncogene amplification addresses a key challenge in gene editing therapies.

The team hypothesizes that this type of cell death could alert immune cells and promote an anti-tumor response. Initial signs of this activation have already been detected, and future work will focus on exploring this further. “Gene editing of amplification in tumors may be a basis for developing precision gene therapies for resistant cancers,” the team affirms.

Researchers have also begun exploring combinations with existing therapies in animal models. Combining gene editing with a chemotherapy drug commonly used for neuroblastoma resulted in more cell death than either treatment alone.

Alejandro Nieto and Marta Martínez-Lage, co-first authors of the work, conclude that “the study demonstrates a novel strategy based on CRISPR that turns the amplification of oncogenes into a vulnerability, triggering the death of only tumor cells, which could open a path to precision therapies for difficult-to-treat tumors.”

Frequently Asked Questions

What are oncogenes?

Oncogenes are genes that, when abnormally behaving, are linked to the development and aggressiveness of cancer.

What is oncogene amplification?

Oncogene amplification refers to a situation where a cell contains a very high number of copies of an oncogene – sometimes dozens or even hundreds.

What role does CRISPR-Cas9 play in this research?

The CRISPR-Cas9 gene editing tool is used to make a cut in the amplified oncogene, leading to accumulated genetic damage and cell death.

Could this research eventually lead to new, more effective cancer treatments that specifically target tumor cells while minimizing harm to healthy tissue?