Gene editing technique helps find cancer's weak spots

March 20, 2017, University of California - San Diego
A network of synthetic-lethal interactions connecting commonly mutated genes to potential drug targets. Credit: UC San Diego Health

Genetic mutations that cause cancer also weaken cancer cells, creating an opportunity for researchers to develop drugs that will selectively kill them, while sparing normal cells. This concept is called "synthetic lethality" because the drug is only lethal to mutated (synthetic) cells. Researchers at UC San Diego School of Medicine and Jacobs School of Engineering developed a new method to search for synthetic-lethal gene combinations.

The technique, published March 20 in Nature Methods, uncovered 120 new opportunities for .

"The ovarian drug olaparib works by synthetic lethality—it inhibits a gene that, when a BRCA gene is also mutated, kills just those ," said John Paul Shen, MD, clinical instructor and postdoctoral fellow at UC San Diego School of Medicine and Moores Cancer Center. "Many other cancers could likely be treated this way as well, but we don't yet know which gene mutation combinations will be synthetic-lethal." Shen was co-first author of the study, along with Dongxin Zhao, PhD, postdoctoral fellow at UC San Diego Jacobs School of Engineering, and Roman Sasik, PhD, computational biologist in the UC San Diego School of Medicine.

To overcome this limitation, the team developed a new method that uses the CRISPR/Cas9 to simultaneously test for thousands of synthetic-lethal interactions. CRISPR/Cas9 works like this: researchers design a "guide" RNA to match the sequence of a specific target gene in a cell. The RNA guides the Cas9 enzyme to the desired spot, where it cuts the DNA. The cell can repair the DNA break, but it does so imprecisely, thereby inactivating the gene.

In this study, the researchers designed a CRISPR/Cas9 system with two guide RNAs: 1) one that targets a that is commonly mutated in cancer and 2) one that targets a gene that could also be disrupted by a cancer drug. They deployed this system against 73 genes in three laboratory cell lines—human cervical cancer, lung cancer and embryonic kidney —for a total of 150,000 gene combinations. Then they measured cell growth and death.

The approach revealed more than 120 new synthetic-lethal interactions.

"Identifying underlying genetic interactions in this way can reveal important functional relationships between , such as contributions to the same protein complex or pathway," co-senior author Trey Ideker, PhD, professor in the UC San Diego School of Medicine, founder of the UC San Diego Center for Computational Biology and Bioinformatics and co-director of the Cancer Cell Map Initiative. "This in turn can impact both our fundamental understanding of biological systems, as well as therapeutics development."

Many of the gene interactions the team identified were synthetic-lethal in just one of the three cell lines tested. This means that synthetic-lethal interactions may be different in different types of cancer. The researchers said this will be an important consideration for future drug development.

"Moving forward, we intend to further refine our technology platform and make it more robust," said co-senior author Prashant Mali, PhD, assistant professor in the Jacobs School of Engineering at UC San Diego. "And we are scaling our cancer genetic networks maps so we can systematically identify new combination therapies."

Explore further: Researchers ID cancer gene-drug combinations ripe for precision medicine

More information: Combinatorial CRISPR–Cas9 screens for de novo mapping of genetic interactions, Nature Methods, nature.com/articles/doi:10.1038/nmeth.4225

Related Stories

Researchers ID cancer gene-drug combinations ripe for precision medicine

July 21, 2016
In an effort to expand the number of cancer gene mutations that can be specifically targeted with personalized therapies, researchers at University of California San Diego School of Medicine and Moores Cancer Center looked ...

CAR T cells more powerful when built with CRISPR, researchers find

February 22, 2017
Researchers from Memorial Sloan Kettering Cancer Center (MSK) have harnessed the power of CRISPR/Cas9 to create more-potent chimeric antigen receptor (CAR) T cells that enhance tumor rejection in mice. The unexpected findings, ...

Researchers identify 'synthetic essentiality' as novel approach for locating cancer therapy targets

February 6, 2017
A new method has been found for identifying therapeutic targets in cancers lacking specific key tumor suppressor genes. The process, which located a genetic site for the most common form of prostate cancer, has potential ...

Researchers chart global genetic interaction networks in human cancer cells

February 2, 2017
Cancer is a heterogeneous disease, with myriad distinct subtypes that differ in their genetic roots. As a result, cancers rely on varied pathways for survival—and respond differently to anticancer agents. The challenge ...

Researchers discover new approach to improve personalized cancer treatments

October 15, 2013
Researchers from the University of Minnesota, Mayo Clinic, and University of Toronto have successfully shown that a new method for targeting mutated cells could create a major breakthrough in a personalized medicine approach ...

Recommended for you

Single blood test screens for eight cancer types

January 18, 2018
Johns Hopkins Kimmel Cancer Center researchers developed a single blood test that screens for eight common cancer types and helps identify the location of the cancer.

Researchers find a way to 'starve' cancer

January 18, 2018
Researchers at Vanderbilt University Medical Center (VUMC) have demonstrated for the first time that it is possible to starve a tumor and stop its growth with a newly discovered small compound that blocks uptake of the vital ...

How cancer metastasis happens: Researchers reveal a key mechanism

January 18, 2018
Cancer metastasis, the migration of cells from a primary tumor to form distant tumors in the body, can be triggered by a chronic leakage of DNA within tumor cells, according to a team led by Weill Cornell Medicine and Memorial ...

Modular gene enhancer promotes leukemia and regulates effectiveness of chemotherapy

January 18, 2018
Every day, billions of new blood cells are generated in the bone marrow. The gene Myc is known to play an important role in this process, and is also known to play a role in cancer. Scientists from the German Cancer Research ...

These foods may up your odds for colon cancer

January 18, 2018
(HealthDay)—Chowing down on red meat, white bread and sugar-laden drinks might increase your long-term risk of colon cancer, a new study suggests.

The pill lowers ovarian cancer risk, even for smokers

January 18, 2018
(HealthDay)—It's known that use of the birth control pill is tied to lower odds for ovarian cancer, but new research shows the benefit extends to smokers or women who are obese.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.