Researchers at the University of Texas have performed genome-wide CRISPR screens to uncover vulnerabilities critical for discovering anticancer drugs.
The new study, published in Science Advances, provides a comprehensive and comparative dataset for genetic interactions between the whole-genome protein-coding genes and a panel of tumour suppressor genes.
Cancer is at least partially a genetic disease, since multiple genetic alterations occur during tumour formation. Among them, oncogenes and tumour suppressor genes are the most prevalent and critical ones, playing essential roles in tumour formation. Exploiting cancer vulnerabilities is critical for the discovery of anticancer drugs. However, tumour suppressors cannot be directly targeted because of their loss of function.
Targeting Tumour Suppressors Genes
For many known driver oncogenes, highly potent and specific inhibitors have been developed. This strategy has been proven to be clinically successful, although cancers may eventually acquire resistance to these drugs.
Tumour suppressor genes participate in many cancer-related processes, including cell-cell adhesion and hypoxia response. However, unlike targetable oncogenes, tumour suppressors are not directly druggable because of their functional loss. These may arise from deletion, loss-of-function mutations, epigenetic silence, and posttranslational regulations.
The team, led by Dr Feng, hypothesised that some tumour suppressors could be targeted to suppress proliferation of cells with deficiency in other tumour suppressors.
To uncover specific vulnerabilities for cells with deficiency in any given tumour suppressor, the researchers performed genome-scale CRISPR loss-of-function screens. The study used a panel of isogenic knockout (KO) cells generated for 12 common tumour suppressors.
Synthetic lethality
Dr Feng and team first focused on the shared synthetic lethality genes. “The concept of synthetic lethality provides an ideal strategy to target cancers with deficiency in certain tumour suppressors”, the team proposed. Synthetic lethality describes a situation in which mutations in two genes together result in cell death, but a mutation in either gene alone does not.
They discovered that cells with loss of certain tumour suppressor genes were prone to be sicker than wild type genes when cells gained mutations. This resulted in DNA repair deficiency or dysregulated nucleotide metabolism.
Nucleotide metabolism is critical for DNA/RNA synthesis, DNA replication, and efficient DNA repair. This supports uncontrolled tumour cell growth, therefore agents targeting nucleotide metabolism are widely used for cancer chemotherapeutics.
Mining this dataset uncovered essential paralog gene pairs, which could be a common mechanism for interpreting synthetic lethality.
The study found that depletion of dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme, is synthetic lethal with VHL KO and BAP1 KO.
Inhibitors of DHODH, such as leflunomide and its active metabolite teriflunomide, have been approved by the U.S. Food and Drug Administration (FDA) for rheumatoid arthritis and multiple sclerosis treatment. Similarly, a new DHODH inhibitor was recently granted orphan drug designation by the FDA and is in a phase 2 clinical trial for the treatment of acute myeloid leukaemia.
The study uncovered that a tumour suppressor gene could be a potential anticancer target for cancers bearing another tumour suppressor gene deficiency, such as the synthetic lethality relationship of TSC2 with STK11, KDM5C with BAP1, and SMARCA4 or ARID1A with PTEN.
The authors note, “This dataset provides valuable information that can be further exploited for targeted cancer therapy”.
Written by Poppy Jayne Morgan
Image Credit: Canva
