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 cancer drug development.
"The ovarian cancer drug olaparib works by synthetic lethality -- it inhibits a gene that, when a BRCA gene is also mutated, kills just those cancer cells," 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 gene editing technique 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 tumor suppressor gene 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 cells -- 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 genes, 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."
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, UC San Diego; Dan Du, Assen Roguev, Nevan Krogan, UC San Francisco; and Lei Qi, Stanford University.
Heather Buschman | EurekAlert!
NIST scientists discover how to switch liver cancer cell growth from 2-D to 3-D structures
17.11.2017 | National Institute of Standards and Technology (NIST)
High speed video recording precisely measures blood cell velocity
15.11.2017 | ITMO University
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
17.11.2017 | Physics and Astronomy
17.11.2017 | Health and Medicine
17.11.2017 | Studies and Analyses