Gene editing used to find cancer’s genetic weak spots – The San Diego Union-Tribune

A UC San Diego-led research team has put the hot gene-editing technology CRISPR/Cas9 to a novel use, finding more than 120 new leads for cancer drugs.

The team inactivated targeted genes in lab-cultured kidney, lung and cervical cancer cancer cells to pinpoint those that kill these cells but leave normal cells unharmed.

With the gene editing technology, large numbers of genes can be tested simultaneously for their effect on cancer, said John Paul Shen, one of the studys lead authors.

The study also found that the weak spots where inactivation kills malignant cells varies according to the cell type.

CRISPR has made the once cumbersome process of gene editing, faster and more precise, leading to comparisons with the impact of the word processor. But in this study, Shen and colleagues turned CRISPR on its head to selectively introduce disabling errors.

Human testing with already approved drugs identified through the research could begin in as little as a year, said Shen, postdoctoral researcher at UC San Diego School of Medicine. Further down the road, new drugs precisely targeted to vulnerable spots in various types of cancer could be developed.

Doctors could rework their cancer therapies to take the findings into account. But more validation of the study findings is needed before that can be done.

This discovery is still preliminary, Shen said. Before you would change what youre doing for a patient, you would need to see that interaction reproduces in other cell types. Ideally, youd like to see it in a mouse model, not just a cell culture.

Each cancer is unique, Shen said, so it would theoretically be possible to develop drugs personalized toward each individual cancer. Of course, this isnt practical. But the next best thing is to identify subtypes of cancers with common vulnerabilities. Patients can be treated with drugs or combinations of drugs that target those vulnerabilities.

The study was published March 20 in Nature Methods. Other co-first authors along with Shen are Dongxin Zhao and Roman Sasik. The senior authors are Trey Ideker and Prashant Mali. It can be found at j.mp/cancercr.

Ideker has developed a model of cancer circuits that link apparently randomly placed cancer-causing mutations into patterns of molecular activity. So a cancer driven by a mutation in one circuit might be stopped by interrupting the downstream effects of that mutation.

In this study, researchers looked for gene pairs that exhibit synthetic lethality. This is when inactivating both genes kills the cells, but if one gene in the pair is active, the cells survive. So cancers driven by a synthetic lethal mutation can be killed by inactivating the other gene in the pair, leaving normal cells unharmed.

Some existing drugs work this way, such as the ovarian cancer drug olaparib, Shen said. Sold under the brand name Lynparza, the drug was approved for in December 2014 for cancers with disabling mutations in the BRCA1 or BRCA2 genes.

And there are many other synthetic-lethal gene combinations yet to be discovered, Shen said, perhaps triggered by existing drugs that werent developed with that effect in mind. Even if only a small fraction can form the base of new drugs, they would greatly expand the range of cancers that can be treated in this way.

To this model, CRISPR brings the ability to test potential synthetic lethal combinations much more quickly and efficiently than disabling genes one at a time.

The CRISPR technology is often used by researchers to repair genetic defects. It allows cutting a precise location in the gene to allow a corrected DNA sequence to be inserted. But in this study, the goal was to break the DNA without supplying a correction. The natural DNA repair mechanisms rejoined the broken ends, introducing errors in the process.

UCSDs Mali and others have adapted CRISPR to rapidly inactivate pairs of genes.

Researchers developed a new way to guide the Cas9 enzyme, which cleaves DNA, to target both a tumor suppressor gene thats often mutated in cancer along with a gene that could be targeted with a cancer drug.

Thats never been done before, in a high throughput, in human cells, Shen said.

After sorting through more than 2,500 gene combinations the scientists found more than 120 new synthetic-lethal interactions.

However, many of these synthetic-lethal interactions occurred in just one of the three cell types tested, the study found. This means the source of the cancer must also be considered in developing drugs by this method.

Finding that this difference in interactions varied by cell types was probably the studys biggest discovery, Shen said.

Now that weve shown that this technology works, we want to move forward and test many more cell types and see what are the synthetic lethal interactions that are conserved (among different cell types), because those are the ones that well want to take into the clinic, he said.

Additional study co-authors include: Jens Luebeck, Amanda Birmingham, Ana Bojorquez-Gomez, Katherine Licon, Kristin Klepper, Daniel Pekin, Alex Beckett, Kyle Sanchez, Alex Thomas, Chih-Chung Kuo, Nathan E Lewis, Aaron N Chang, Jason F Kreisberg, all of UC San Diego; Dan Du, Assen Roguev, Nevan Krogan, all of UC San Francisco; and Lei Qi, Stanford University.

This research was funded in part, by the National Institutes of Health, Burroughs Wellcome Fund, March of Dimes Foundation, Sidney Kimmel Foundation, California Institute for Regenerative Medicine, UC San Diego Clinical and Translational Research Institute Grant, and Novo Nordisk Foundation Center for Biosustainability.

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Gene editing used to find cancer's genetic weak spots - The San Diego Union-Tribune