Breakthrough in Cancer Research: New CRISPR Platform Identifies Genes Linked to Drug Resistance
Researchers have made a significant discovery using a novel whole-genome CRISPR screening platform, uncovering a previously unidentified gene that contributes to lymphoma cells’ resistance to a commonly used cancer medication, as well as several genes that can accelerate tumor growth. The findings, published in Science Advances, have the potential to reveal new therapeutic targets for combating drug resistance.
The CRISPR technique has transformed cancer research by enabling scientists to manipulate specific genes and examine their role in disease. Unlike traditional CRISPR methods, which typically involve disrupting or deleting genes, the research team utilized a new tool called Partita, which activates gene activity. This CRISPR activation technology allows for the systematic switching on of every gene in the mouse genome, one at a time, in both cellular and live models, providing a full understanding of the genes that drive disease.
Overcoming drug resistance is a major challenge in cancer treatment. By identifying the genes responsible for this phenomenon, researchers may uncover new opportunities to block resistance and enhance the effectiveness of existing treatments. According to Marco Herold, PhD, CEO of the Olivia Newton-John Cancer Research Institute (ONJCRI) and head of the La Trobe University School of Cancer Medicine, “We know that many therapy resistance issues happen because of genes being unregulated, even after the most successful treatments like targeted therapies and CAR T-cell therapy.” He added, “With Partita, we found the usual genetic suspects mediating resistance, but also many others that represent potential new treatment options.”
The research team employed Partita to conduct extensive screens in models of aggressive lymphoma, searching for genes whose activation could influence the response of cancer cells to treatment. Their findings revealed that the Irx5 gene, when activated, drives resistance to venetoclax, a widely used blood cancer medication. Further experiments demonstrated that Irx5 enables cancer cells to survive treatment by increasing levels of a protein involved in cell survival. Additionally, in live mice, Partita facilitated the identification of three genes – Runx2, Runx3, and Csf1r – that accelerate the growth of MYC-driven lymphoma.
Eddie La Marca, PhD, a postdoctoral researcher at ONJCRI, noted, “Currently, MYC-driven lymphomas are challenging to treat, and Partita helped find cancer-promoting genes that could be switched off to slow or stop tumor growth in these cancers.”
Partita was designed as a high-coverage, whole-genome mouse CRISPR activation library, utilizing 10 guide RNAs directed at each transcriptional start site. This enables researchers to systematically screen genes across the mouse genome, rather than testing individual candidates one at a time. The researchers believe that Partita could expand the application of CRISPR activation in functional genomics, providing a systematic approach to investigating the consequences of gene activation in cells and living organisms.
