New Drug Targets for Cancer Identified Using CRISPR

New Drug Targets for Cancer Identified Using CRISPR

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Highlights:
  • A research team, from Jacob's School of Engineering, used the genome editing tool CRISPR to identify gene interactions in synthetic or mutated cancer cells
  • The scientists identified 120 novel synthetic-lethal gene combinations
  • Synthetic lethality is a method for drug therapy whereby potential new drugs can be designed
A research team from UC San Diego School of Medicine and Jacobs School of Engineering has identified a novel method of finding mutated (synthetic) cells. These 'synthetic cells' are cells that have undergone genetic mutations and which have developed into cancers; however, the mutations also tend to weaken the cells. This is called 'synthetic lethality' and this concept can be used for drug therapy. The results of the study were published in Nature Methods, with over 120 new strategies for cancer drug development.
New Drug Targets for Cancer Identified Using CRISPR

A clinical instructor and postdoctoral fellow at UC San Diego School of Medicine and Moores Cancer Center, Dr. John Paul Shen said that the drug Olaparib, given for ovarian cancer, works on the basis of synthetic lethality. This drug blocks a gene which leads to the death of BRCA mutated cancer cells. Dr. Shen, who is the co-first author of the study, further stated that many cancers could be treated using this method but there is currently no comprehensive list of the gene combinations that are synthetic-lethal.

CRISPR/Cas9 System

The process of identifying gene combinations that are lethal can be laborious; however, this process is reduced by using the gene editing tool CRISPR/Cas9. This popular tool can test for thousands of synthetic-lethal combinations at the same time.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated system or Cas genes are required for adaptive immunity among certain bacterial species, which allows these organisms to react to the invading genetic material. The gene editing tools were discovered in E. coli in 1980 but their function did not become evident till 2007. It was shown that S. thermophilus could develop a resistance towards infection by a bacteriophage by integrating a fragment of the genome of the infectious agent into its locus.

Types of CRISPR

There are three different types of CRISPR which have been identified among which type 2 is well known. In the type 2 form of CRIPSR
  • The DNA from the invading plasmids or viruses are cut into smaller fragments
  • These fragments are then incorporated into the CRISPR locus in between short repeats
  • There is transcription of the loci; the transcripts are then processed to result in small RNAs
  • These small RNAs guide the endonucleases which target the DNA of the invading virus or plasmid based on complementarity
  • The Cas9 protein is required for gene silencing
  • The protein is also required for the synthesis of CRISPR RNA as well as for the destruction of the target DNA
In the current study, the CRISPR/Cas9 system was used to generate two guide RNAs
  • Targeting the commonly mutated tumor suppressing gene
  • Targeting a gene that can be disrupted by a drug for cancer
The gene editing tool was used on three cell lines, human cervical cancer cells, lung cancer cells and embryonic kidney cells and covered 73 genes. There were more than 150,000 gene combinations which were targeted. After treatment with the CRISPR/Cas9 system, cell growth and death were analyzed. The study identified more than 120 novel synthetic-lethal combinations.

A professor at the UC San Diego School of Medicine and co-director of the Cancer Cell Map Initiative, Dr. Trey Ideker, who is also the co-author of the study, said that identifying the genetic interactions using the CRISPR/Cas9 system will aid in revealing functional relationships of genes, associated with a protein complex or a pathway. Dr. Trey, also the founder of the UC San Diego Center for Computational Biology and Bioinformatics said that these findings could be used to improve basic understanding of various biological systems and could also be used for developing drug therapy for cancer.

Synthetic-lethal Interactions

The synthetic-lethal interactions that were identified were found in just one of the three cell lines that were tested, indicating that the interactions were different for the different types of cancer. This is a critical understanding for drug development.

Dr. Prashant Mali, co-senior author of the study and an assistant professor at UC San Diego's Jacobs School of Engineering, said that the scientists would be refining their technology platform to make it comprehensive, with new cancer genetic network maps being set up to identify new combination therapies systematically.

CRISPR in Cancer Research

Dr. Si Chen and colleagues published a paper in the International Journal of Biological Sciences titled "CRISPR-Cas9: from Genome Editing to Cancer Research". The development of cancer involves multiple steps and is associated with innate mutations as well as mutations that are acquired. These mutations lead to the functional abnormality seen in cancer and they determine the progress of cancer. The CRISPR-associated 9 (CRISPR-Cas9) system provides a genome editing approach which is convenient.

CRISPR is utilized in cancer studies in the following ways
  • Loss of function of gene-screening invivo
  • Gain of function of gene-screening invivo
  • Acceleration of cancer in animal models for research purposes
  • Potential use in gene therapy for cancer
The applicability of CRISPR in cancer studies is numerous, but the current research involving the use of CRISPR to identify systemic lethal interactions will aid in developing more effective cancer drugs.

References:
  1. CRISPR-Cas9: from Genome Editing to Cancer Research - (https:www.ncbi.nlm.nih.gov/pmc/articles/PMC5166485/)
Source: Medindia

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